pH Mapping of Gliomas Using Quantitative Chemical Exchange Saturation Transfer MRI: Quasi-Steady-State, Spillover-, and MT-Corrected Omega Plot Analysis.

BACKGROUND: Quantitative in-situ pH mapping of gliomas is important for therapeutic interventions, given its significant association with tumor progression, invasion, and metastasis. Although chemical exchange saturation transfer (CEST) offers a noninvasive way for pH imaging based on the pH-dependent exchange rate (ksw ), the reliable quantification of ksw in glioma remains constrained due to technical challenges. PURPOSE: To quantify the pH of gliomas by measuring the proton exchange rate through optimized omega plot analysis. STUDY TYPE: Prospective. PHANTOMS/ANIMAL MODEL/SUBJECTS: Creatine and murine brain lysates phantoms, six rats with glioma xenograft model, and three patients with World Health Organization grade 2-4 gliomas. FIELD STRENGTH/SEQUENCE: 11.7 T, 7.0 T, CEST imaging, T2 -weighted (T2 W) imaging, and T1 -mapping. ASSESSMENT: Omega plot analysis, quasi-steady-state (QUASS) analysis, multi-pool Lorentzian fitting, amine and amide concentration-independent detection, pH enhanced method with the combination of amide and guanidyl (pHenh ), and magnetization transfer ratio (MTR) were utilized for pH metric quantification. The clinical outcomes were determined through radiologic follow-up and histopathological analysis. STATISTICAL TESTS: Mann-Whitney U test was performed to compare glioma with normal tissue, and Pearson's correlation analysis was used to assess the relationship between ksw and other parameters. RESULTS: In vitro experiments reveal that the determined ksw at 2 ppm increases exponentially with pH (creatine phantoms: ksw = 106 + 0.147 × 10(pH-4.198) ; lysates: ksw = 185.1 + 0.101 × 10(pH-3.914) ). Omega plot analysis exhibits a linear correlation between 1/MTRRex and 1/ω1 2 in the glioma xenografts (R2 > 0.98) and glioma patients (R2 > 0.99). The exchange rate in the rat glioma decreases compared to the contralateral normal tissue (349.46 ± 30.40 s-1 vs. 403.54 ± 51.01 s-1 , P = 0.025), while keeping independence from changes in concentration (r = 0.5037, P = 0.095). Similar pattern was observed in human data. DATA CONCLUSION: Utilizing QUASS-based, spillover-, and MT-corrected omega plot analysis for the measurement of exchange rates, offers a feasible method for quantifying pH within glioma. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 1.

Assessment of early anthracycline-induced cardiotoxicity and liver injury with T2 and T2* mapping in rabbit models.

OBJECTIVES: To evaluate the early prevalence of anthracycline-induced cardiotoxicity (AIC) and anthracycline-induced liver injury (AILI) using T2 and T2* mapping and to explore their correlations. MATERIALS AND METHODS: The study included 17 cardiotoxic rabbits that received weekly injections of doxorubicin and magnetic resonance imaging (MRI) every 2 weeks for 10 weeks. Cardiac function and T2 and T2* values were measured on each period. Histopathological examinations for two to five rabbits were performed after each MRI scan. The earliest sensitive time and the threshold of MRI parameters for detecting AIC and AILI based on these MRI parameters were obtained. Moreover, the relationship between myocardial and liver damage was assessed. RESULTS: Early AIC could be detected by T2 mapping as early as the second week and focused on the 7th, 11th, and 12th segments of left ventricle. The cutoff value of 46.64 for the 7th segment had the best diagnostic value, with an area under the curve (of 0.767, sensitivity of 100%, and specificity of 52%. T2* mapping could detect the change in iron content for early AIC at the middle interventricular septum and AILI as early as the sixth week (p = 0.014, p = 0.027). The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver (r = 0.39, p = 0.002). CONCLUSION: T2 and T2* mapping showed value one-stop assessment of AIC and AILI and could obtain the earliest MRI diagnosis point and optimal parameter thresholds for these conditions. CLINICAL RELEVANCE STATEMENT: Anthracycline-induced cardiotoxicity could be detected by T2 mapping as earlier as the second week, mainly focusing on the 7th, 11th, and 12th segments of left ventricle. Combined with T2* mapping, hepatoxicity and supplementary cardiotoxicity were assessed by one-stop scan. KEY POINTS: • MRI screening time of cardiotoxicity was as early as the second week with focusing on T2 values of the 7th, 11th, and 12th segments of left ventricle. • T2* mapping could be used as a complement to T2 mapping to evaluate cardiotoxicity and as an effective index to detect iron change in the early stages of chemotherapy. • The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver, indicating that iron content in the liver and heart increased with an increase in the chemotherapeutic drugs.

Assessment of early anthracycline-induced cardiotoxicity using segmental strain of cardiac magnetic resonance compared with global strain and functional parameters: an animal study.

Background: The identification of anthracycline-induced cardiotoxicity holds significant importance in guiding subsequent treatment strategies, and recent research has demonstrated the efficacy of cardiac magnetic resonance (CMR) global strain analysis for its diagnosis. On the other hand, it is noteworthy that abnormal global myocardial strain may exhibit a temporal delay due to different cardiac movement in each segment of the left ventricle. To address this concern, this study aims to assess the diagnostic utility of CMR segmental strain analysis as an early detection method for cardiotoxicity. Methods: A serials of CMR scans were performed in 18 adult males New Zealand rabbits at baseline time (n=15), followed by scans at week 2 (n=15), week 4 (n=9), week 6 (n=6), and week 8 (n=5) after each week's anthracycline injection. Additionally, following each CMR scan, two to three rabbits were euthanized for pathological comparison. Cardiac functional parameters, global peak strain parameters, segmental peak strain parameters of the left ventricle, and the presence of myocardial cells damage were obtained. A mixed linear model was employed to obtain the earliest CMR diagnostic time. Receiver operating characteristic (ROC) analysis was performed to get the parameter threshold indicative of cardiotoxicity. Results: The left ventricular ejection fraction decreased at week 8 (P=0.002). There were no statistical differences in global strain throughout the experiment period (P>0.05). Regarding segmental strain analysis, the peak segmental radial strain of the apical lateral wall exhibited a decrease starting from week 2 and reached its lowest point at this week (P=0.011). Conversely, peak segmental circumferential strain of the apical anterior wall showed an increase at week 2 and reached its peak at week 6 (P=0.026). The cutoff strain value by ROC analysis for these two walls were 46.285 and -16.920, with the respective areas under the curve (AUC) 0.593 [specificity =0.267, sensitivity =1.000, 95% confidence interval (CI): 0.471-0.777] and 0.764 (specificity =0.733, sensitivity =0.784, 95% CI: 0.511-0.816). Peak segmental longitudinal strain of the apical anterior and apical lateral wall showed relatively delayed changes, occurring in the 4th week (P=0.030 and P=0.048), the cutoff values for these strains were -12.415 and -15.960, with corresponding AUCs of 0.645 (specificity =0.333, sensitivity =0.955, 95% CI: 0.495-0.795) and 0.717 (specificity =0.433, sensitivity =0.955, 95% CI: 0.566-0.902), respectively. Notably, the myocardial injury was also observed at the corresponding periods. Conclusions: Based on experimental evidence, the peak segmental strain of the apical lateral and anterior wall, as determined by CMR, demonstrated an earlier detection of anthracycline-induced cardiotoxicity compared to peak global strain and cardiac function.

Intra-Operative Definition of Glioma Infiltrative Margins by Visualizing Immunosuppressive Tumor-Associated Macrophages.

Accurate delineation of glioma infiltrative margins remains a challenge due to the low density of cancer cells in these regions. Here, a hierarchical imaging strategy to define glioma margins by locating the immunosuppressive tumor-associated macrophages (TAMs) is proposed. A pH ratiometric fluorescent probe CP2-M that targets immunosuppressive TAMs by binding to mannose receptor (CD206) is developed, and it subsequently senses the acidic phagosomal lumen, resulting in a remarkable fluorescence enhancement. With assistance of CP2-M, glioma xenografts in mouse models with a tumor-to-background ratio exceeding 3.0 for up to 6 h are successfully visualized. Furthermore, by intra-operatively mapping the pH distribution of exposed tissue after craniotomy, the glioma allograft in rat models is precisely excised. The overall survival of rat models significantly surpasses that achieved using clinically employed fluorescent probes. This work presents a novel strategy for locating glioma margins, thereby improving surgical outcomes for tumors with infiltrative characteristics.

Diagnostic value of Kaiser score combined with breast vascular assessment from breast MRI for the characterization of breast lesions.

Objectives: The Kaiser scoring system for breast magnetic resonance imaging is a clinical decision-making tool for diagnosing breast lesions. However, the Kaiser score (KS) did not include the evaluation of breast vascularity. Therefore, this study aimed to use KS combined with breast vascular assessment, defined as KS*, and investigate the effectiveness of KS* in differentiating benign from malignant breast lesions. Methods: This retrospective study included 223 patients with suspicious breast lesions and pathologically verified results. The histopathological diagnostic criteria were according to the fifth edition of the WHO classification of breast tumors. The KS* was obtained after a joint evaluation combining the original KS and breast vasculature assessment. The receiver operating characteristic (ROC) curve was used for comparing differences in the diagnostic performance between KS* and KS, and the area under the receiver operating characteristic (AUC) was compared. Results: There were 119 (53.4%) benign and 104 (46.6%) malignant lesions in total. The overall sensitivity, specificity, and accuracy of increased ipsilateral breast vascularity were 69.2%, 76.5%, and 73.1%, respectively. The overall sensitivity, specificity, and accuracy of AVS were 82.7%, 76.5%, and 79.4%, respectively. For all lesions included the AUC of KS* was greater than that of KS (0.877 vs. 0.858, P = 0.016). The largest difference in AUC was observed in the non-mass subgroup (0.793 vs. 0.725, P = 0.029). Conclusion: Ipsilaterally increased breast vascularity and a positive AVS sign were significantly associated with malignancy. KS combined with breast vascular assessment can effectively improve the diagnostic ability of KS for breast lesions, especially for non-mass lesions.

Deep Learning-Assisted Quantitative Susceptibility Mapping as a Tool for Grading and Molecular Subtyping of Gliomas.

This study aimed to explore the value of deep learning (DL)-assisted quantitative susceptibility mapping (QSM) in glioma grading and molecular subtyping. Forty-two patients with gliomas, who underwent preoperative T2 fluid-attenuated inversion recovery (T2 FLAIR), contrast-enhanced T1-weighted imaging (T1WI + C), and QSM scanning at 3.0T magnetic resonance imaging (MRI) were included in this study. Histopathology and immunohistochemistry staining were used to determine glioma grades, and isocitrate dehydrogenase (IDH) 1 and alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) subtypes. Tumor segmentation was performed manually using Insight Toolkit-SNAP program (www.itksnap.org). An inception convolutional neural network (CNN) with a subsequent linear layer was employed as the training encoder to capture multi-scale features from MRI slices. Fivefold cross-validation was utilized as the training strategy (seven samples for each fold), and the ratio of sample size of the training, validation, and test dataset was 4:1:1. The performance was evaluated by the accuracy and area under the curve (AUC). With the inception CNN, single modal of QSM showed better performance in differentiating glioblastomas (GBM) and other grade gliomas (OGG, grade II-III), and predicting IDH1 mutation and ATRX loss (accuracy: 0.80, 0.77, 0.60) than either T2 FLAIR (0.69, 0.57, 0.54) or T1WI + C (0.74, 0.57, 0.46). When combining three modalities, compared with any single modality, the best AUC/accuracy/F1-scores were reached in grading gliomas (OGG and GBM: 0.91/0.89/0.87, low-grade and high-grade gliomas: 0.83/0.86/0.81), predicting IDH1 mutation (0.88/0.89/0.85), and predicting ATRX loss (0.78/0.71/0.67). As a supplement to conventional MRI, DL-assisted QSM is a promising molecular imaging method to evaluate glioma grades, IDH1 mutation, and ATRX loss. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00087-6.

Retrograde percutaneous coronary intervention of chronic total occlusion via discontinuous septal channels.

OBJECTIVES: The study aims to investigate the safety and feasibility of retrograde CTO intervention via collateral connection grade 0 (CC-0) septal channel and to identify predictors of collateral tracking failure. BACKGROUND: Guidewire crossing a collateral channel is a critical step for successful retrograde percutaneous coronary intervention (PCI) of chronic total occlusion (CTO). METHODS: Retrograde PCI was attempted in 122 cases of CTO with CC-0 septal collaterals from December 2018 to May 2021. A hydrophilic polymer coating guidewire was used for crossing all intended CC-0 collaterals. A multivariable logistic regression analysis was performed to identify the predictors of guidewire tracking failure via the CC-0 collaterals. RESULTS: Successful guidewire tracking via CC-0 septal channel was achieved in 98 (80.3%) of 122 cases. The independent predictors of CC-0 septal channel guidewire tracking failure included well-developed non-septal collateral (OR: 5.297, 95% CI: 1.107-25.353, p = 0.037) and the ratio length of posterior descending artery (PDA) versus the distance of PDA ostium to cardiac apex ≤2/3 (OR: 3.970, 95% CI: 1.454-10.835, p = 0.007). Collateral perforation, target vessel perforation, and cardiac tamponade occurred in 5 (4.1%), 3 (2.5%), and 6 (4.9%) cases, respectively. There were no complications requiring emergency cardiac surgery or revascularization of nontarget vessel. CONCLUSIONS: Retrograde PCI via CC-0 septal channels with a hydrophilic polymer-coated guidewire is feasible and safe in patients with CTO. Well-developed nonseptal collaterals and short PDA length influence the procedure success and the risk of guidewire tracking failure via CC-0 septal channels.

The extract of Curcumae Longae Rhizoma suppresses angiogenesis via VEGF-induced PI3K/Akt-eNOS-NO pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcumae Longae Rhizoma (CLR) is a safe natural herbal medicine, and which has been widely used for centuries as functional food and health products, but its effects on angiogenesis and related underlying mechanism remain unclear. AIM OF THE STUDY: The abnormal angiogenesis is closely related with various diseases, and therefore the precise control of angiogenesis is of great importance. The well-known angiogenic factor, vascular endothelial growth factor (VEGF), mediates angiogenesis and induces multiple signalling pathways via binding to VEGF receptor (VEGFR). The attenuation of VEGF-triggered angiogenic-related signalling pathways may relieve various diseases through suppression of angiogenesis. Here, we aimed to elucidate that CLR extract could exert striking anti-angiogenic activities both in vitro and in vivo. MATERIALS AND METHODS: The viability of human umbilical vascular endothelial cell (HUVEC) was examined by LDH and MTT assays. Migrative and invasive ability of the endothelial cells were independently evaluated by wound healing and transwell assays. The activities of CLR extract on in vitro angiogenesis was tested by tube formation assay. In vivo vascularization was determined by using zebrafish embryo model in the present of CLR extract. Western blotting was applied to determine the phosphorylated levels of VEGFR2, PI3K, AKT and eNOS. Besides, the levels of nitric oxide (NO) and reactive oxygen species (ROS) were separately evaluated by Griess assay and 2'7'-dichlorofluorescein diacetate reaction. In addition, the cell migrative ability of cancer cell was estimated by using cultured human colon carcinoma cells (HT-29 cell line), and immunofluorescence assay was applied to evaluate the effect of CLR extract on nuclear translocation of NF-κB p65 subunit in the VEGF-treated HT-29 cultures. RESULTS: CLR extract significantly suppressed a series of VEGF-mediated angiogenic responses, including endothelial cell proliferation, migration, invasion, and tube formation. Moreover, CLR extract reduced in vivo sub-intestinal vessel formation in zebrafish embryo model. Mechanistically, the extract of CLR attenuated the VEGF-triggered signalling, as demonstrated by decreased level of phosphorylated VEGFR2 and subsequently inactivated its downstream regulators, e.g. phospho-PI3K, phospho-AKT and phospho-eNOS. The production of NO and formation of ROS were markedly inhibited in HUVECs. Furthermore, CLR extract suppressed cell migration and NF-κB translocation in cultured HT-29 cells. CONCLUSIONS: These preclinical findings demonstrate that the extract of CLR remarkably attenuates angiogenesis and which has great potential as a natural drug candidate with excellent anti-angiogenic activity.

Resveratrol, an Inhibitor Binding to VEGF, Restores the Pathology of Abnormal Angiogenesis in Retinopathy of Prematurity (ROP) in Mice: Application by Intravitreal and Topical Instillation.

Retinopathy of prematurity (ROP) is a severe eye disease leading to blindness. Abnormal vessel formation is the pathological hallmark of neovascular ROP. In forming vessels, vascular endothelial growth factor (VEGF) is an important stimulator. The current anti-ROP therapy has focused on bevacizumab, a monoclonal antibody against VEGF, and pazopanib, a tyrosine kinase inhibitor on the VEGF receptor (VEGFR). Several lines of evidence have proposed that natural compounds may be more effective and safer for anti-VEGF function. Resveratrol, a common natural compound, binds to VEGF and blocks its interaction with VEGFR, thereafter suppressing angiogenesis. Here, we evaluate the efficacy of intravitreal injection, or topical instillation (eye drops), of resveratrol into the eyes of mice suffering from oxygen-induced retinopathy, i.e., developing ROP. The treatment of resveratrol significantly relieved the degree of vascular distortion, permeability and hyperplasia; the efficacy could be revealed by both methods of resveratrol application. In parallel, the treatments of resveratrol inhibited the retinal expressions of VEGF, VEGFR and CD31. Moreover, the applied resveratrol significantly relieved the damage caused by oxygen radicals through upregulating the level of superoxide dismutase (SOD) and downregulating the level of malondialdehyde (MDA) in the retina. Taken together, the potential therapeutic benefit of resveratrol in pro-angiogenic diseases, including retinopathy, can be considered.

Comparison of contrast-enhanced T1-weighted imaging using DANTE-SPACE, PETRA, and MPRAGE: a clinical evaluation of brain tumors at 3 Tesla.

BACKGROUND: We aimed to compare the performance of three contrast-enhanced T1-weighted three-dimensional (3D) magnetic resonance (MR) sequences to detect brain tumors at 3 Tesla. The three sequences were: (I) delay alternating with nutation for tailored excitation sampling perfection with application-optimized contrasts using different flip angle evolution (DANTE-SPACE), (II) pointwise encoding time reduction with radial acquisition (PETRA), and (III) magnetization-prepared rapid acquisition with gradient echo (MPRAGE). METHODS: This study involved 77 consecutive patients, including 34 patients with known primary brain tumors and 43 patients suspected of intracranial metastases. All patients underwent each of the three sequences with comparable spatial resolution and acquisition time post-injection. Signal-to-noise ratios (SNRs) for gray matter (GM) and white matter (WM), contrast-to-noise ratios (CNRs) for lesion/GM, lesion/WM, and GM/WM were quantitatively compared. Two radiologists determined the total number of enhancing lesions by consensus. Intraclass correlation coefficients (ICCs) between the two radiologists for metastases presence, qualitative ratings for image quality, and acoustic noise level of each sequence were assessed. RESULTS: Among the three sequences, SNRs and CNRs between lesions and surrounding parenchyma were highest using DANTE-SPACE, but CNRWM/GM was the lowest with DANTE-SPACE. SNRs for PETRA images were significantly higher than those for MPRAGE (P<0.001). CNRs between lesions and surrounding parenchyma were similar for PETRA and MPRAGE (P>0.05). Significantly more brain metastases were detected with DANTE-SPACE (n=94) compared with MPRAGE (n=71) and PETRA (n=72). The ICCs were 0.964 for MPRAGE, 0.975 for PETRA, and 0.973 for DANTE-SPACE. Qualitative scores for lesion imaging using DANTE-SPACE were significantly higher than those obtained with PETRA and MPRAGE (P=0.002 and P=0.004, respectively). The acoustic noise level for PETRA (64.45 dB) was significantly lower than that for MPRAGE (78.27 dB, P<0.01) and DANTE-SPACE (80.18 dB, P<0.01). CONCLUSIONS: PETRA achieves comparable detection of brain tumors with MPRAGE and is preferred for depicting osseous metastases and meningeal enhancement. DANTE-SPACE with blood vessel suppression showed improved detection of cerebral metastases compared with MPRAGE and PETRA, which could be helpful for the differential diagnosis of tumors.

Intelligent SERS Navigation System Guiding Brain Tumor Surgery by Intraoperatively Delineating the Metabolic Acidosis.

Surgeons face challenges in intraoperatively defining margin of brain tumors due to its infiltrative nature. Extracellular acidosis caused by metabolic reprogramming of cancer cells is a reliable marker for tumor infiltrative regions. Although the acidic margin-guided surgery shows promise in improving surgical prognosis, its clinical transition is delayed by having the exogenous probes approved by the drug supervision authority. Here, an intelligent surface-enhanced Raman scattering (SERS) navigation system delineating glioma acidic margins without administration of exogenous probes is reported. With assistance of this system, the metabolites at the tumor cutting edges can be nondestructively transferred within a water droplet to a SERS chip with pH sensitivity. Homemade deep learning model automatically processes the Raman spectra collected from the SERS chip and delineates the pH map of tumor resection bed with increased speed. Acidity correlated cancer cell density and proliferation level are demonstrated in tumor cutting edges of animal models and excised tissues from glioma patients. The overall survival of animal models post the SERS system guided surgery is significantly increased in comparison to the conventional strategy used in clinical practice. This SERS system holds the promise in accelerating clinical transition of acidic margin-guided surgery for solid tumors with infiltrative nature.

Hepatic Artery Injection of 131I-Metuximab Combined with Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Prospective Nonrandomized, Multicenter Clinical Trial.

This prospective nonrandomized, multicenter clinical trial was performed to investigate the efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 mo in the TACE + 131I-metuximab group (n = 160) and 3 mo in the TACE group (n = 160) (hazard ratio, 0.55; 95% CI, 0.43-0.70; P < 0.001). The median overall survival was 28 mo in the TACE + 131I-metuximab group and 19 mo in the TACE group (hazard ratio, 0.62; 95% CI, 0.47-0.82; P = 0.001). Conclusion: TACE + 131I-metuximab showed a greater antirecurrence benefit, significantly improved the 5-y survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression.

Tumor-initiating cells (TIC) are associated with tumor initiation, growth, metastasis, and recurrence. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a TIC marker in many cancers, including breast cancer. However, the molecular mechanisms underlying ALDH1A1 functions in solid tumors remain largely unknown. Here we demonstrate that ALDH1A1 enzymatic activity facilitates breast tumor growth. Mechanistically, ALDH1A1 decreased the intracellular pH in breast cancer cells to promote phosphorylation of TAK1, activate NFκB signaling, and increase the secretion of GM-CSF, which led to myeloid-derived suppressor cell expansion and immunosuppression. Furthermore, the ALDH1A1 inhibitor disulfiram and chemotherapeutic agent gemcitabine cooperatively inhibited breast tumor growth and tumorigenesis by purging ALDH+ TICs and activating T-cell immunity. These findings elucidate how active ALDH1A1 modulates the immune system to promote tumor development, highlighting new therapeutic strategies for malignant breast cancer. SIGNIFICANCE: ALDH1A1 enzyme activity induces MDSC expansion and triggers a procancer immune microenvironment to facilitate breast cancer progression, providing a novel therapeutic vulnerability in this disease.

AUCseg: An Automatically Unsupervised Clustering Toolbox for 3D-Segmentation of High-Grade Gliomas in Multi-Parametric MR Images.

The segmentation of high-grade gliomas (HGG) using magnetic resonance imaging (MRI) data is clinically meaningful in neurosurgical practice, but a challenging task. Currently, most segmentation methods are supervised learning with labeled training sets. Although these methods work well in most cases, they typically require time-consuming manual labeling and pre-trained models. In this work, we propose an automatically unsupervised segmentation toolbox based on the clustering algorithm and morphological processing, named AUCseg. With our toolbox, the whole tumor was first extracted by clustering on T2-FLAIR images. Then, based on the mask acquired with whole tumor segmentation, the enhancing tumor was segmented on the post-contrast T1-weighted images (T1-CE) using clustering methods. Finally, the necrotic regions were segmented by morphological processing or clustering on T2-weighted images. Compared with K-means, Mini-batch K-means, and Fuzzy C Means (FCM), the Gaussian Mixture Model (GMM) clustering performs the best in our toolbox. We did a multi-sided evaluation of our toolbox in the BraTS2018 dataset and demonstrated that the whole tumor, tumor core, and enhancing tumor can be automatically segmented using default hyper-parameters with Dice score 0.8209, 0.7087, and 0.7254, respectively. The computing time of our toolbox for each case is around 22 seconds, which is at least 3 times faster than other state-of-the-art unsupervised methods. In addition, our toolbox has an option to perform semi-automatic segmentation via manually setup hyper-parameters, which could improve the segmentation performance. Our toolbox, AUCseg, is publicly available on Github. (https://github.com/Haifengtao/AUCseg).

Detection and Classification of Breast Lesions With Readout-Segmented Diffusion-Weighted Imaging in a Large Chinese Cohort.

Objectives: To evaluate the performance of readout-segmented echo-planar imaging DWI (rs-EPI DWI) in detecting and characterizing breast cancers in a large Chinese cohort with comparison to dynamic contrast-enhanced MRI (DCE-MRI). Methods: The institutional review board approved this retrospective study with waived written informed consent. A total of 520 women (mean age, 43.1- ± 10.5-years) were included from July 2013 to October 2019. First, the ability of rs-EPI DWI in detecting breast lesions identified by DCE-MRI was evaluated. The lesion conspicuity of rs-EPI-DWI and DCE-MRI was compared using the Wilcoxon signed rank test. With pathology as a reference, the performance of rs-EPI DWI and DCE-MRI in distinguishing breast cancers was evaluated and compared using the Chi-square test. Results: Of 520 women, 327/520 (62.9%) patients had 423 lesions confirmed by pathology with 203 benign and 220 malignant lesions. The rs-EPI DWI can detect 90.8% (659/726) (reader 1) and 90.6% (663/732) (reader 2) of lesions identified by DCE-MRI. The lesion visibility was superior for DCE-MRI than rs-EPI-DWI (all p < 0.05). With pathology as a reference, the sensitivities and specificities of rs-EPI DWI in diagnosing breast cancers were 95.9% (211/220) and 85.7% (174/203) for reader 1 and 97.7% (215/220) and 86.2% (175/203) for reader 2. No significant differences were found for the performance of DCE-MRI and rs-EPI DWI in discriminating breast cancers (all p > 0.05). Conclusions: Although with an inferior lesion visibility, rs-EPI DWI can detect about 90% of breast lesions identified by DCE-MRI and has comparable diagnostic capacity to that of DCE-MRI in identifying breast cancer.

Preferential Targeting Cerebral Ischemic Lesions with Cancer Cell-Inspired Nanovehicle for Ischemic Stroke Treatment.

The poor drug delivery to cerebral ischemic regions is a key challenge of ischemic stroke treatment. Inspired by the intriguing blood-brain barrier (BBB)-penetrating ability of 4T1 cancer cells upon their brain metastasis, we herein designed a promising biomimetic nanoplatform by camouflaging a succinobucol-loaded pH-sensitive polymeric nanovehicle with a 4T1 cell membrane (MPP/SCB), aiming to promote the preferential targeting of cerebral ischemic lesions to attenuate the ischemia/reperfusion injury. In transient middle cerebral artery occlusion (tMCAO) rat models, MPP/SCB could be preferentially delivered to the ischemic hemisphere with a 4.79-fold higher than that in the normal hemisphere. Moreover, MPP/SCB produced notable enhancement of microvascular reperfusion in the ischemic hemisphere, resulting in a 69.9% reduction of infarct volume and showing remarkable neuroprotective effects of tMCAO rats, which was superior to the counterpart uncamouflaged nanovehicles (PP/SCB). Therefore, this design provides a promising nanoplatform to target the cerebral ischemic lesions for ischemic stroke therapy.

Preliminary demonstration of in vivo quasi-steady-state CEST postprocessing-Correction of saturation time and relaxation delay for robust quantification of tumor MT and APT effects.

PURPOSE: Chemical exchange saturation transfer (CEST) MRI is versatile for measuring the dilute labile protons and microenvironment properties. However, the use of insufficiently long RF saturation duration (Ts) and relaxation delay (Td) may underestimate the CEST measurement. This study proposed a quasi-steady-state (QUASS) CEST analysis for robust CEST quantification. METHODS: The CEST signal evolution was modeled as a function of the longitudinal relaxation rate during Td and spin-lock relaxation rate during Ts, from which the QUASS-CEST effect is derived. Numerical simulation and in vivo rat glioma MRI experiments were conducted at 11.7 T to compare the apparent and QUASS-CEST results obtained under different Ts/Td of 2 seconds/2 seconds and 4 seconds/4 seconds. Magnetization transfer and amide proton transfer effects were resolved using a multipool Lorentzian fitting and evaluated in contralateral normal tissue and tumor regions. RESULTS: The simulation showed the dependence of the apparent CEST effect on Ts and Td, and such reliance was mitigated with the QUASS algorithm. Animal experiment results showed that the apparent magnetization transfer and amide proton transfer effects and their contrast between contralateral normal tissue and tumor regions increased substantially with Ts and Td. In comparison, the QUASS magnetization transfer and amide proton transfer effects and their difference between contralateral normal tissue and tumor exhibited little dependence on Ts and Td. In addition, the apparent magnetization transfer and amide proton transfer were significantly smaller than the corresponding QUASS indices (P < .05). CONCLUSION: The QUASS-CEST algorithm enables robust CEST quantification and offers a straightforward approach to standardize CEST experiments.

Systematic analysis of the basic/helix-loop-helix (bHLH) transcription factor family in pummelo (Citrus grandis) and identification of the key members involved in the response to iron deficiency.

BACKGROUND: Iron (Fe) deficiency is a common problem in citrus production. As the second largest superfamily of transcription factors (TFs), the basic/helix-loop-helix (bHLH) proteins have been shown to participate in the regulation of Fe homeostasis and a series of other biological and developmental processes in plants. However, this family of members in citrus and their functions in citrus Fe deficiency are still largely unknown. RESULTS: In this study, we identified a total of 128 CgbHLHs from pummelo (Citrus grandis) genome that were classified into 18 subfamilies by phylogenetic comparison with Arabidopsis thaliana bHLH proteins. All of these CgbHLHs were randomly distributed on nine known (125 genes) and one unknown (3 genes) chromosomes, and 12 and 47 of them were identified to be tandem and segmental duplicated genes, respectively. Sequence analysis showed detailed characteristics of their intron-exon structures, bHLH domain and conserved motifs. Gene ontology (GO) analysis suggested that most of CgbHLHs were annotated to the nucleus, DNA-binding transcription factor activity, response to abiotic stimulus, reproduction, post-embryonic development, flower development and photosynthesis. In addition, 27 CgbHLH proteins were predicted to have direct or indirect protein-protein interactions. Based on GO annotation, RNA sequencing data in public database and qRT-PCR results, several of CgbHLHs were identified as the key candidates that respond to iron deficiency. CONCLUSIONS: In total, 128 CgbHLH proteins were identified from pummelo, and their detailed sequence and structure characteristics and putative functions were analyzed. This study provides comprehensive information for further functional elucidation of CgbHLH genes in citrus.

A pH ratiometrically responsive surface enhanced resonance Raman scattering probe for tumor acidic margin delineation and image-guided surgery.

Surgery remains the mainstay for most solid tumor treatments. However, surgeons face challenges in intra-operatively identifying invasive tumor margins due to their infiltrative nature. Incomplete excision usually leads to early recurrence, while aggressive resection may injure adjacent functional tissues. Herein, we report a pH responsive ratiometric surface-enhanced Raman scattering (SERRS) probe that determined physiological pHs with a high sensitivity and tissue penetration depth via an innovative mechanism named spatial orientation induced intramolecular energy transfer (SOIET). Due to the positive correlation between tumor acidity and malignancy, an acidic margin-guided surgery strategy was implemented in live animal models by intra-operatively assessing tissue pH/malignancy of the suspicious tissues in tumor cutting edges. This surgery remarkably extended the survival of animal models and minimized their post-surgical complications, showing promise in precisely identifying invasive tumor boundaries and achieving a balance between maximum tumor debulking and minimal functional impairment.

Surface-Enhanced Resonance Raman Scattering-Guided Brain Tumor Surgery Showing Prognostic Benefit in Rat Models.

Glioma is the most frequent form of malignant brain tumors. Surgical debulking is a major strategy for glioma treatment. However, there is a great challenge for the neurosurgeons to intraoperatively identify the true margins of glioma because of its infiltrative nature. Tumor residues or microscopic satellite foci left in the resection bed are the main reasons leading to early recurrence as well as poor prognosis. In this study, a surface-enhanced resonance Raman scattering (SERRS) probe was developed to intraoperatively guide glioma resection. In this probe, molecular reporters with absorptive maxima at the near-infrared wavelength range were covalently functionalized on the surface of gold nanostars. This SERRS probe demonstrated an ultrahigh sensitivity with a detection limit of 5.0 pM in aqueous solution. By the development of glioma xenografts in a mouse dorsal skin window chamber, extravasation of this probe from leaky tumor vasculature as functions of time and distance to tumor boundary was investigated. Importantly, the invasive margin of the tumor xenograft was demarcated by this probe with a high signal-to-background ratio. Preoperative magnetic resonance imaging (MRI) first defined the position of orthotopic glioma xenografts in the brain of rat models, and the craniotomy plan was designed. The brain tumor was then excised intraoperatively step-by-step with the assistance of a handheld Raman scanner till the Raman signals of the probe completely disappeared in the resection bed. Notably, longitudinal MRI showed that SERRS-guided surgery significantly reduced the tumor recurrence rate and improved the overall survival of rat models compared with the white light-guided surgery. Overall, this work demonstrates the prognostic benefit of SERRS-guided glioma surgery in animal models. Because delineation of tumor-invasive margins is a common challenge faced by the surgeons, this SERRS probe with a picomolar detection limit holds the promise in improving the surgical outcome of different types of infiltrated tumors.