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Overproduced reactive oxygen species and the induced oxidative stress and neuroinflammation often result in secondary injury, which is associated with unfavorable prognosis in traumatic brain injury (TBI). Unfortunately, current medications cannot effectively ameliorate the secondary injury at traumatic sites. Here, it is reported that intrinsically bioactive multifunctional nanocomposites (ANG-MnEMNPs-Cur, AMEC) mediate antioxidation and anti-neuroinflammation for targeted TBI theranostics, which are engineered by loading the neuroprotective agent curcumin on angiopep-2 functionalized and manganese doped eumelanin-like nanoparticles. After intravenous delivery, efficient AMEC accumulation is observed in lesions of TBI mice models established by controlled cortical impact method, evidenced by T

Malignant glioma is the most common brain tumor in adults. Despite the great advances in anti-glioma treatments which have led to significant improvement in clinical outcomes, tumor recurrence remains the major cause of mortality. Increased cancer cell stemness and invasiveness are correlated with glioma progression. By searching the Cancer Genome Atlas, we showed that the expression of miR-7156-3p is significantly decreased in glioma tissues compared to the normal brain, and the decreased level of miR-7156-3p is closely correlated with glioma grade and patient survival. Clinical study consistently confirmed that miR-7156-3p is negatively correlated with glioma grade. Cell culture and animal experiments revealed that inhibition of miR-7156-3p effectively stimulates glioma cell stemness, invasion, and growth. In contrast, the augmentation of miR-7156-3p inhibits these phenotypes. Using Next-generation sequencing combined with target prediction approach, Homeobox D13 (HOXD13) is identified as the target gene of miR-7156-3p and further validated by luciferase reporter assay and cell transfection experiments. Additional in vitro and animal experiments demonstrated that miR-7156-3p regulates glioma cell stemness, invasion, and growth by mediating HOXD13. In conclusion, our findings provide new insight into the regulation of glioma stemness and invasiveness and may propose a potential strategy for anti-glioma treatment. Moreover, miR-7156-3p may serve as a candidate biomarker for predicting glioma progression in clinical practice.

The current study aimed to evaluate the clinical practice for hemodynamic tissue signature (HTS) method in IDH genotype prediction in three groups derived from high-grade gliomas. Preoperative MRI examinations of 44 patients with known grade and IDH genotype were assigned into three study groups: glioblastoma multiforme, grade III, and high-grade gliomas. Perfusion parameters were analyzed and were used to automatically draw the four reproducible habitats (high-angiogenic enhancing tumor habitats, low-angiogenic enhancing tumor habitats, infiltrated peripheral edema habitats, vasogenic peripheral edema habitats) related to vascular heterogeneity. These four habitats were then compared between inter-patient with IDH mutation and their wild-type counterparts at these three groups, respectively. The discriminating potential for HTS in assessing IDH mutation status prediction was assessed by ROC curves. Compared with IDH wild type, IDH mutation had significantly decreased relative cerebral blood volume (rCBV) at the high-angiogenic enhancing tumor habitats and low-angiogenic enhancing tumor habitats. ROC analysis revealed that the rCBVs in habitats had great ability to discriminate IDH mutation from their wild type in all groups. In addition, the Kaplan-Meier survival analysis yielded significant differences for the survival times observed from the populations dichotomized by low ( 4.31) rCBV in the low-angiogenic enhancing tumor habitat. The HTS method has been proven to have high prediction capabilities for IDH mutation status in high-grade glioma patients, providing a set of quantifiable habitats associated with tumor vascular heterogeneity. • The HTS method has a high accuracy for molecular stratification prediction for all subsets of HGG. • The HTS method can give IDH mutation–related hemodynamic information of tumor-infiltrated and vasogenic edema. • IDH-relevant rCBV difference in habitats will be a great prognosis factor in HGG.

Rationale: Tumor vascular normalization (TVN) is emerging to enhance the efficacy of anticancer treatment in many cancers including glioblastoma (GBM). However, a common and severe challenge being currently faced is the transient TVN effect, hampering the sustained administration of anticancer therapy during TVN window. Additionally, the lack of non-contrast agent-based imaging biomarkers to monitor TVN process postpones the clinical translation of TVN strategy. In this study, we investigated whether dual inhibition of VEGF and the glycolytic activator PFKFB3 could reinforce the TVN effect in GBM. Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) and intravoxel incoherent motion (IVIM)-MRI were performed to monitor TVN process and to identify whether IVIM-MRI is a candidate or complementary imaging biomarker for monitoring TVN window without exogenous contrast agent administration. Methods: Patient-derived orthotopic GBM xenografts in mice were established and treated with bevacizumab (BEV), 3PO (PFKFB3 inhibitor), BEV+3PO dual therapy, or saline. The vascular morphology, tumor hypoxia, and lactate level were evaluated before and at different time points after treatments. Doxorubicin was used to evaluate chemotherapeutic efficacy and drug delivery. Microarray of angiogenesis cytokines and western blotting were conducted to characterize post-treatment molecular profiling. TVN process was monitored by DCE- and IVIM-MRI. Correlation analysis of pathological indicators and MRI parameters was further analyzed. Results: Dual therapy extended survival and delayed tumor growth over each therapy alone, concomitant with a decrease of cell proliferation and an increase of cell apoptosis. The dual therapy reinforces TVN effect, thereby alleviating tumor hypoxia, reducing lactate production, and improving the efficacy and delivery of doxorubicin. Mechanistically, several angiogenic cytokines and pathways were downregulated after dual therapy. Notably, dual therapy inhibited Tie1 expression, the key regulator of TVN, in both endothelial cells and tumor cells. DCE- and IVIM-MRI data showed that dual therapy induced a more homogenous and prominent TVN effect characterized by improved vascular function in tumor core and tumor rim. Correlation analysis revealed that IVIM-MRI parameter D * had better correlations with TVN pathological indicators compared with the DCE-MRI parameter K trans. Conclusions: Our results propose a rationale to overcome the current limitation of BEV monotherapy by integrating the synergistic effects of VEGF and PFKFB3 blockade to enhance chemotherapy efficacy through a sustained TVN effect. Moreover, we unveil IVIM-MRI parameter D * has much potential as a complementary imaging biomarker to monitor TVN window more precisely without exogenous contrast agent injection.

Introduction and objective Precisely and sensitively diagnosing diseases especially early and accurate tumor diagnosis in clinical magnetic resonance (MR) scanner is a highly demanding but challenging task. Gadolinium (Gd) chelate is the most common T 1 magnetic resonance imaging (MRI) contrast agent at present. However, traditional Gd-chelates are suffering from low relaxivity, which hampers its application in clinical diagnosis. Currently, the development of nano-sized Gd based T 1 contrast agent, such as incorporating gadolinium chelate into nanocarriers, is an attractive and feasible strategy to enhance the T 1 contrast capacity of Gd chelate. The objective of this study is to improve the T 1 contrast ability of Gd-chelate by synthesizing nanoparticles (NPs) for accurate and early diagnosis in clinical diseases. Methods Reverse microemulsion method was used to coat iron oxide (IO) with tunable silica shell and form cores of NPs IO@SiO2 at step one, then Gd-chelate was loaded on the surface of silica-coated iron oxide NPs. Finally, Gd-based silica coating magnetite NPs IO@SiO2-DTPA-Gd was developed and tested the ability to detect tumor cells on the cellular and in vivo level. Results The r 1 value of IO@SiO2-DTPA-Gd NPs with the silica shell thickness of 12 nm was about 33.6 mM-1s-1, which was approximately 6 times higher than Gd-DTPA, and based on its high T 1 contrast ability, IO@SiO2-DTPA-Gd NPs could effectively detect tumor cells on the cellular and in vivo level. Conclusion Our findings revealed the improvement of T 1 relaxation was not only because of the increase of molecular tumbling time caused by the IO@SiO2 nanocarrier but also the generated magnetic field caused by the IO core. This nanostructure with high T 1 contrast ability may open a new approach to construct high-performance T 1 contrast agent.

Purpose: This study aimed to investigate the potential of computed tomography (CT) imaging features and texture analysis to distinguish bronchiolar adenoma (BA) from adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma (MIA). Materials and Methods: Fifteen patients with BA, 38 patients with AIS, and 36 patients with MIA were included in this study. Clinical data and CT imaging features of the three lesions were evaluated. Texture features were extracted from the thin-section unenhanced CT images using Artificial Intelligence Kit software. Then, multivariate logistic regression analysis based on selected texture features was employed to distinguish BA from AIS/MIA. Receiver operating characteristics curves were performed to determine the diagnostic performance of the features. Results: By comparison with AIS/MIA, significantly different CT imaging features of BA included nodule type, tumor size, and pseudo-cavitation sign. Among them, pseudo-cavitation sign had a moderate diagnostic value for distinguishing BA and AIS/MIA (AUC: 0.741 and 0.708, respectively). Further, a total of 396 quantitative texture features were extracted. After comparation, the top six texture features showing the most significant difference between BA and AIS or MIA were chosen. The ROC results showed that these key texture features had a high diagnostic value for differentiating BA from AIS or MIA, among which the value of a comprehensive model with six selected texture features was the highest (AUC: 0.977 or 0.976, respectively) for BA and AIS or MIA. These results indicated that texture analyses can effectively improve the efficacy of thin-section unenhanced CT for discriminating BA from AIS/MIA. Conclusion: CT texture analysis can effectively improve the efficacy of thin-section unenhanced CT for discriminating BA from AIS/MIA, which has a potential clinical value and helps pathologist and clinicians to make diagnostic and therapeutic strategies.

Background aims Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment strategy in solid tumors. In vivo cell tracking techniques can help us better understand the infiltration, persistence and therapeutic efficacy of CAR T cells. In this field, magnetic resonance imaging (MRI) can achieve high-resolution images of cells by using cellular imaging probes. MRI can also provide various biological information on solid tumors. Methods The authors adopted the amino alcohol derivatives of glucose-coated nanoparticles, ultra-small superparamagnetic particles of iron oxide (USPIOs), to label CAR T cells for non-invasive monitoring of kinetic infiltration and persistence in glioblastoma (GBM). The specific targeting CARs included anti-human epidermal growth factor receptor variant III and IL13 receptor subunit alpha 2 CARs. Results When using an appropriate concentration, USPIO labeling exerted no negative effects on the biological characteristics and killing efficiency of CAR T cells. Increasing hypointensity signals could be detected in GBM models by susceptibility-weighted imaging MRI ranging from 3 days to 14 days following the injection of USPIO-labeled CAR T cells. In addition, nanoparticles and CAR T cells were found on consecutive histopathological sections. Moreover, diffusion and perfusion MRI revealed significantly increased water diffusion and decreased vascular permeability on day 3 after treatment, which was simultaneously accompanied by a significant decrease in tumor cell proliferation and increase in intercellular tight junction on immunostaining sections. Conclusion These results establish an effective imaging technique that can track CAR T cells in GBM models and validate their early therapeutic effects, which may guide the evaluation of CAR T-cell therapies in solid tumors.

Mn(iv)-Based nanoparticles (NPs) are effective in improving tumor oxygenation (hypoxia) and reducing endogenous hydrogen peroxide and acidity in the tumor region. However, the optimized reduction conditions of conventional Mn(iv)-based NPs are generally reported at pH ≤ 6.5, while the usual pH range of the tumor microenvironment (TME) is 6.5-7.0. The dissatisfactory imaging performance in the weakly acidic environment may limit their further application in tumor diagnosis. In this study, Mn(iii) was introduced in a nanoplatform, because it is reduced into Mn(ii) in weakly acidic environments. Arg-Gly-Asp (RGD) peptide-decorated bovine serum albumin (BSA) was employed as the stabilizer and scaffold to fabricate Mn(iii)- and Mn(iv)-integrated nanocomposites (RGD-BMnNPs) with suitable size, good stability, and excellent biocompatibility. The as-prepared NPs showed clear contrast enhancement at pH 6.5-6.9 in vitro as well as sensitive and rapid T1-weighted imaging performance within the tumor region in a glioblastoma (U87MG) orthotopic model, owing to the intrinsic disproportionation reaction of Mn(iii) in the weakly acidic environment. In addition, these NPs could be used for efficient siRNA delivery. They showed superior advantages in this process, including increased tumour uptake, improved tumor accumulation and enhanced therapeutic effects with the modulation of the TME. These novel albumin-stabilized manganese-based NPs combined with efficient drug delivery capacity hold great potential to serve as intelligent theranostic agents for further clinical translation.

Background and Purpose— Accumulated evidence suggests that hemin—a breakdown product of hemoglobin—plays a pivotal role in the inflammatory injuries that result after hemorrhagic stroke through the Toll Like Receptor 2-Toll Like Receptor 4 signal pathway. However, the mechanism of how hemin triggers neuronal necroptosis directly after intracranial hemorrhage (ICH) is still an area of active research. As animal model and preclinical studies have shown, the recombinant interleukin-1 receptor antagonist (IL-1RA) improves clinical outcomes after stroke. As such, we have chosen to investigate the mechanism of how IL-1RA exerts protective effect in hemin-induced neuronal necroptosis after ICH. Methods— Our ICH model was induced by hemin injection in C57BL/6 mice and IL-1R1 −/− mice. In addition, we used primary cultured neurons to assess hemin-induced cell death. Co-immunoprecipitation, immunoblot, immunofluorescent staining, neurological deficit scores, and brain water content were used to study the mechanisms of IL-1R1 modulation in neuronal necroptosis both in vitro and in vivo. Results— Free hemin could mediate neuronal necroptosis directly by assembling necrosome complex and then to trigger cell death. This phenomenon was driven by IL-1R1 as IL-1R1 can form a complex with necrosome. After treatment with IL-1RA, both the expression and translocation of the necrosome decreased while disruption of the interaction between IL-1R1 and RIP1/RIP3 (receptor interacting protein 1/3) increased neuron survival. In addition, the IL-1R1–deficient mice demonstrated lower levels of necrosome components, including RIP1, RIP3, and MLKL (mixed lineage kinase domain-like protein), compared with control groups after hemin treatment. In addition, the neurological deficit scores, brain water content, and inflammatory response were all also reduced in the IL-1R1–deficient mice. Conclusions— Functional inhibition of the interaction between IL-1R1 and the necrosome complex improves neuron survival and promotes the recovery of neurological function in experimental ICH. Targeting IL-1R1/RIP1/RIP3 assembly could be a promising therapeutic strategy for patients with ICH.

Glomeruloid vascular proliferation (GVP) is a diagnostic hallmark and links to aggressive behavior, therapy resistance and poor prognosis in glioblastoma (GBM). It lacks clinical approaches to predict and monitor its formation and dynamic change. Yet the mechanism of GVPs also remains largely unknown. Using an in situ GBM xenograft mouse model, combined clinical MRI images of pre-surgery tumor and pathological investigation, we demonstrated that the inhibition of tissue factor (TF) decreased GVPs in Mouse GBM xenograft model. TF shRNA reduced microvascular area and diameter, other than bevacizumab. TF dominantly functions via PAR2/HB-EGF-dependent activation under hypoxia in endothelial cells (ECs), resulting in a reduction of GVPs and cancer cells invasion. TF expression strongly correlated to GVPs and microvascular area (MVA) in GBM specimens from 56 patients, which could be quantitatively evaluated in an advanced MRI images system in 33 GBM patients. This study presented an approach to assess GVPs that could be served as a MRI imaging biomarker in GBM and uncovered a molecular mechanism of GVPs.

Gliomas possess complex and heterogeneous vasculatures with abnormal hemodynamics. Despite considerable advances in diagnostic and therapeutic techniques for improving tumor management and patient care in recent years, the prognosis of malignant gliomas remains dismal. Perfusion-weighted magnetic resonance imaging techniques that could noninvasively provide superior information on vascular functionality have attracted much attention for evaluating brain tumors. However, nonconsensus imaging protocols and postprocessing analysis among different institutions impede their integration into standard-of-care imaging in clinic. And there have been very few studies providing a comprehensive evidence-based and systematic summary. This review first outlines the status of glioma theranostics and tumor-associated vascular pathology and then presents an overview of the principles of dynamic contrast-enhanced MRI (DCE-MRI) and dynamic susceptibility contrast-MRI (DSC-MRI), with emphasis on their recent clinical applications in gliomas including tumor grading, identification of molecular characteristics, differentiation of glioma from other brain tumors, treatment response assessment, and predicting prognosis. Current challenges and future perspectives are also highlighted.

Neovascularization is required in high-grade glioma (HGG). The objective of this study was to explore neovascularization-related genes and their corresponding MRI biomarkers during the early-growth stage of HGG. Tumor tissues from 30 HGG patients underwent perfusion MRI scanning prior to surgery were used to establish orthotopic xenograft models, pathologically analyze the tumor vasculature and perform transcriptome sequencing. The cases were divided into two groups based on whether the xenograft was successfully established. Microvascular density and BMPER, CXCL10, and HOXA9 expression of surgical specimens in the xenograft-forming group was significantly elevated and the microvascular diameter was significantly reduced, in vitro inhibition of BMPER, CXCL10, or HOXA9 in the glioma stem cell significantly suppressed its tube formation abilities. The in vivo experiment showed that BMPER was highly expressed in the early tumor growth phase (20 days), CXCL10 and HOXA9 expression was elevated with tumor progress, and spatially associated with tumor vasculature. Perfusion weighted MRI (PWI-MRI) derived parameters, rCBV, rCBF, Ktrans, and Vp, were also increased in the xenograft-forming group. In conclusion BMPER, CXCL10, and HOXA9 promote early tumor growth and progression by stimulating neovascularization of primary HGG. The rCBV, rCBF, Ktrans, and Vp can be used as imaging biomarkers to predict the expression statuses of these genes.

Laparoscopic lateral pelvic tumor dissection (LLPTD) for transobturator tumors may be technically challenging due to the requirement for sufficient operative space. The present study discusses a technique modification with combination of the laparoscopic approach and hand-assisted (HA) open surgery for patients with large obturator masses. LLPTD was performed using the combined approach, defined as HA-LLPTD, with one case treated. According to this technique, a combined working space is constructed based on the outreached laparoscopic space and open extraperitoneal approach, followed by HA-LLPTD. Finally, a literature review was performed to retrospectively evaluate 17 cases of obturator tumors, in terms of tumor type and operative approach. The tumor in the present case was successfully and completely resected, without any obvious intra- and post-operative complications. Based on the literature review, the majority of the cases were benign (~75%) and originated from neurological tissue (~50%). The selection of the operative approach was either open or minimally invasive (50% each). HA-LLPTD allows experienced urological laparoscopic surgeons to safely and completely perform obturator surgery without obstruction of the obturator foramen or formation of intraperitoneal adhesions and associated complications. Therefore, HA-LLPTD may be more useful for transobturator tumor resection compared with the conventional intraperitoneal approach.

Objectives Vessel size imaging (VSI) could reveal average microvessel diameter. The aim was to investigate microvascular characteristics and the efficacy of VSI in lower-grade glioma (LGG) grading and subtype differentiation based on 2016 classification of central nervous system tumours. Methods Fifty-seven LGG (grade II/III, 36/21) patients who received VSI examination before surgery were retrospectively analysed. The average (Rmean) and maximum (Rmax) vessel size indexes were obtained. The long (VDmax) and short (VDmin) vascular diameter, microvascular area (MVA) and density (MVD) were obtained using paraffin specimens. The patients were divided into grades II and III, and histological and molecular subtypes. The differences among microvascular parameters of different subtypes and grades were compared. Two-sample t-test, analysis of variance test, Mann-Whitney test, the Kruskal-Wallis test and Pearson correlation analysis were used for statistics. Results Rmean, Rmax, VDmin, VDmax, and MVA were higher in grade-III than in grade-II LGGs (p < 0.05) in each type except the isocitrate dehydrogenase (IDH) mutant with 1p/19q-intact type. For grade II, the IDH mutant with 1p/19q co-deleted and IDH wildtype possessed more dominant angiogenesis than IDH mutant with 1p/19q-intact type, revealed by lower Rmean, Rmax and VDmin while higher MVD for the former (p < 0.05), the same as oligodendroglioma versus astrocytoma. Rmean and Rmax correlated with VDmin (r = 0.804, 0.815, p < 0.05), VDmax (r = 0.766, 0.774, p < 0.05) and MVA (r = 0.755, 0.759, p < 0.05), respectively, while they had no correlation with MVD (r = -0.085, -0.080, p > 0.05). Conclusions VSI holds great potential for non-invasively revealing microvascular characteristics of LGGs pre-surgery and differentiating their grades and molecular subtypes. Key Points • VSI can assist in differentiating grade-II and -III gliomas. • The IDH gene and 1p/19q chromosome may influence the angiogenesis in grade-II gliomas. • VSI is valuable for differentiating the molecular subtypes of grade-II gliomas. Electronic supplementary material The online version of this article (10.1007/s00330-018-5738-y) contains supplementary material, which is available to authorized users.

Background Presurgical glioma grading by dynamic contrast-enhanced MRI (DCE-MRI) has unresolved issues. Purpose The aim of this study was to investigate the ability of textural features derived from pharmacokinetic model-based or model-free parameter maps of DCE-MRI in discriminating between different grades of gliomas, and their correlation with pathological index. Study Type Retrospective. Subjects Forty-two adults with brain gliomas. Field Strength/Sequence 3.0T, including conventional anatomic sequences and DCE-MRI sequences (variable flip angle T1-weighted imaging and three-dimensional gradient echo volumetric imaging). Assessment Regions of interest on the cross-sectional images with maximal tumor lesion. Five commonly used textural features, including Energy, Entropy, Inertia, Correlation, and Inverse Difference Moment (IDM), were generated. Results All textural features of model-free parameters (initial area under curve [IAUC], maximal signal intensity [Max SI], maximal up-slope [Max Slope]) could effectively differentiate between grade II (n = 15), grade III (n = 13), and grade IV (n = 14) gliomas (P

Objective Tissue Factor (TF) has been well established in angiogenesis, invasion, metastasis, and prognosis in glioma. A noninvasive assessment of TF expression status in glioma is therefore of obvious clinical relevance. Dynamic contrast-enhanced (DCE) MRI parameters have been used to evaluate microvascular characteristics and predict molecular expression status in tumors. Our aim is to investigate whether quantitative DCE-MRI parameters could assess TF expression in glioma. Materials and methods Thirty-two patients with histopathologically diagnosed supratentorial glioma who underwent DCE-MRI were retrospectively recruited. Extended Tofts linear model was used for DCE-MRI post-processing. Hot-spot, whole tumor cross-sectional approaches, and histogram were used for analysis of model based parameters. Four serial paraffin sections of each case were stained with TF, CD105, CD34 and α-Sooth Muscle Actin, respectively for evaluating the association of TF and microvascular properties. Pearson correlation was performed between percentage of TF expression area and DCE-MRI parameters, multiple microvascular indexes. Results Volume transfer constant (Ktrans) hot-spot value best correlated with TF (r = 0.886, p Conclusion Our results indicate that Ktrans may serve as a potential clinical imaging biomarker to predict TF expression status preoperatively in gliomas.

BACKGROUND Prostate-specific membrane antigen (PSMA) is a highly specific biological marker and treatment target for prostate cancer. So ultrasound molecular imaging using PSMA antibody-loaded targeted nanoscale microbubbles (MBs) may contribute to the early diagnosis of prostate cancer. METHODS PSMA monoclonal antibody-loaded targeted nanoscale MBs were prepared using biotin–avidin technology. Antibody binding was evaluated with immunofluorescence. Using MKN45 gastric cancer cells as controls, the targeting capability of the targeted MBs was observed in prostate cancer cells (LNCaP and C4-2) under optical microscope. Contrast enhancement was monitored by an ultrasound system in C4-2, LNCaP, and MKN45 transplanted tumors in nude mice. The arrival time, time to peak, peak intensity, and duration of contrast enhancement of targeted and blank nanoscale MBs were compared and analyzed. RESULTS Targeted PSMA monoclonal antibody-loaded nanoscale MBs were successfully synthesized. These MBs were stable and could specifically bind to LNCaP and C4-2 cells in vitro but did not bind to MKN45 cells. There were significant differences in peak intensity and duration of contrast enhancement between targeted and blank nanoscale MBs in both transplanted prostate tumors (P

Heng Liu,1,2 Xiao Chen,1 Wei Xue,1 Chengchao Chu,2 Yu Liu,2 Haipeng Tong,1 Xuesong Du,1 Tian Xie,1 Gang Liu,2 Weiguo Zhang1,3 1Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 2State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, 3Chongqing Clinical Research Center for Imaging and Nuclear Medicine, Chongqing, People’s Republic of China Abstract: The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma. Keywords: epidermal growth factor-like domain-1, tissue factor, iron oxide nanoparticles, MRI, glioma

Background G protein–coupled receptor kinase type 4 ( GRK 4) plays a vital role in the long‐term control of blood pressure (BP) and sodium excretion by regulating renal G protein–coupled receptor phosphorylation, including dopamine type 1 receptor (D 1 R). Ultrasound‐targeted microbubble destruction ( UTMD ) is a promising method for gene delivery. Whether this method can deliver GRK 4 small interfering RNA (si RNA) and lower BP is not known. Methods and Results BP, 24‐hour sodium excretion, and urine volume were measured after UTMD ‐targeted GRK 4 si RNA delivery to the kidney in spontaneously hypertensive rats. The expression levels of GRK 4 and D 1 R were determined by immunoblotting. The phosphorylation of D 1 R was investigated using immunoprecipitation. The present study revealed that UTMD ‐mediated renal GRK 4 si RNA delivery efficiently reduced GRK 4 expression and lowered BP in spontaneously hypertensive rats, accompanied by increased sodium excretion. The increased sodium excretion might be accounted for by the UTMD regulation of D 1 R phosphorylation and function in spontaneously hypertensive rats. Further analysis showed that, although UTMD had no effect on D 1 R expression, it reduced D 1 R phosphorylation in spontaneously hypertensive rats kidneys and consequently increased D 1 R‐mediated natriuresis and diuresis. Conclusions Taken together, these study results indicate that UTMD ‐targeted GRK 4 si RNA delivery to the kidney effectively reduces D 1 R phosphorylation by inhibiting renal GRK 4 expression, improving D 1 R‐mediated natriuresis and diuresis, and lowering BP, which may provide a promising novel strategy for gene therapy for hypertension.

To facilitate prostate cancer imaging using targeted molecules, we constructed ultrasonic nanobubbles coupled with specific anti-PSMA (prostate specific membrane antigen) nanobodies, and evaluated their in vitro binding capacity and in vivo imaging efficacy. The “targeted” nanobubbles, which were constructed via a biotin-streptavidin system, had an average diameter of 487.60 ± 33.55 nm and carried the anti-PSMA nanobody as demonstrated by immunofluorescence. Microscopy revealed targeted binding of nanobubbles in vitro to PSMA-positive cells. Additionally, ultrasonography indicators of nanobubble imaging (including arrival time, peak time, peak intensity and enhanced duration) were evaluated for the ultrasound imaging in three kinds of animal xenografts (LNCaP, C4-2 and MKN45), and showed that these four indicators of targeted nanobubbles exhibited significant differences from blank nanobubbles. Therefore, this study not only presents a novel approach to target prostate cancer ultrasonography, but also provides the basis and methods for constructing small-sized and high-efficient targeted ultrasound nanobubbles.

In this study, we aimed to prepare a novel type of microbubble (MB), protamine cationic nanobubble (NB), to provide a new vector for tumor gene therapy. We prepared cationic NBs with protamine and other lipid components using mechanical oscillation. The protamine cationic NBs had a mean diameter of 521.2 ± 37.57 nm, a zeta potential of +18.5 mV, and a gene-carrying capacity of 15.69 μg androgen receptor (AR) siRNA per 10(8) NBs. The cationic NBs exhibited superior contrast enhancement for in vivo imaging compared with SonoVue (Bracco, Geneva, Switzerland), and their physical properties did not change significantly after 1 wk; meanwhile, the transfection efficiency of the cationic NBs in androgen-independent prostate cancer cells mediated by ultrasound irradiation was better than that of liposomes (82.17 ± 7.4% vs. 55.04 ± 5.4%, p 0.01). Therefore, the protamine cationic NB can be considered for use as a novel type of gene-loading MB for ultrasound imaging and MB-mediated gene therapy of tumors.

Prostate-specific membrane antigen (PSMA) is a highly specific biological marker and treatment target for prostate cancer. So ultrasound molecular imaging using PSMA antibody-loaded targeted nanoscale microbubbles (MBs) may contribute to the early diagnosis of prostate cancer.PSMA monoclonal antibody-loaded targeted nanoscale MBs were prepared using biotin-avidin technology. Antibody binding was evaluated with immunofluorescence. Using MKN45 gastric cancer cells as controls, the targeting capability of the targeted MBs was observed in prostate cancer cells (LNCaP and C4-2) under optical microscope. Contrast enhancement was monitored by an ultrasound system in C4-2, LNCaP, and MKN45 transplanted tumors in nude mice. The arrival time, time to peak, peak intensity, and duration of contrast enhancement of targeted and blank nanoscale MBs were compared and analyzed.Targeted PSMA monoclonal antibody-loaded nanoscale MBs were successfully synthesized. These MBs were stable and could specifically bind to LNCaP and C4-2 cells in vitro but did not bind to MKN45 cells. There were significant differences in peak intensity and duration of contrast enhancement between targeted and blank nanoscale MBs in both transplanted prostate tumors (P 0.05). Among the three types of transplanted tumors with targeted nanoscale MBs, the peak intensity was significantly higher in prostate tumors (LNCaP and C4-2) than in gastric tumors (MKN45) (P 0.05).PSMA monoclonal antibody-loaded targeted nanoscale MBs can target and bind to prostate cancer cells specifically and allow for obvious contrast enhancement in vivo. Therefore, this study lays a foundation for early diagnosis and targeted therapy for prostate cancer.

Nanobubbles as a type of ultrasound contrast agent have attracted much interest in recent years due to their many advantages, such as strong penetrating power and high stability. However, there is still insufficient morphological evidence concerning gas-filled nanobubbles in tumor tissue spaces and tumor angiogenesis. We used a gastric cancer xenograft as an example to study this question. Nanobubbles with a particle size of 435.2 ± 60.53 nm were prepared and compared with SonoVue® microbubbles in vitro and in vivo, and they exhibited a superior contrast imaging effect. After excluding the impact of the nanobubbles in blood vessels through saline flush, we used an ultrasound burst and frozen sectioning to investigate the distribution of nanobubbles in the gastric cancer xenografts and confirmed this by transmission electron microscopy. Preliminary results showed that the nanobubbles were able to pass through the gaps between the endothelial cells in the tumor vascular system to enter the tissue space. These findings could provide morphological evidence for extravascular ultrasound imaging of tumors and serve as a foundation for the application of nanobubbles in extravascular tumor-targeted ultrasonic diagnostics and therapy.

Background Ganglioneuroma is a rare benign tumor originating from the sympathetic nerves, and its origination from the trigeminal nerves is even rarer. Only 4 cases of ganglioneuroma originating from the trigeminal nerve have previously been reported, and these studies only reported conventional MRI manifestations. To our knowledge, the advanced MRI features of trigeminal ganglioneuroma have not been reported thus far. Case presentation This study reports a case of trigeminal ganglioneuroma in the left cerebellopontine angle. Advanced MRI showed the following tumor characteristics: significantly increased perfusion on perfusion imaging; isointense on diffusion-weighted imaging, whorled appearance within the tumor and no significant signs of damage to the white matter fiber tracts in the fractional anisotropy color map, and compare to the adjacent brain tissue, Choline didn’t show markedly elevation, and N-acetylaspartate peak showed slightly reduction on magnetic resonance spectroscopy. The tumor was completely resected, and the diagnosis of ganglioneuroma was confirmed by postoperative pathological examination. Conclusion This case demonstrates the conventional as well as advanced MRI manifestations of this rare extra-axial tumor, which have never been previously reported. In addition, we reviewed the literature to demonstrate the advanced MRI features of trigeminal ganglioneuroma, in order to aid preoperative diagnosis and differentiation.