Publications by authors named "Jingwen Yao"

37 Publications

A study of 3D radial density adapted trajectories for sodium imaging.

Magn Reson Imaging 2021 Jul 13. Epub 2021 Jul 13.

Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, CA, USA.

Sodium imaging typically employs ultrashort echo time radial, density adapted and cones trajectories to capture the rapidly decaying short T2 signal. The present study considers the parameter choices involved in the use of these trajectories in terms of their impact on the resolution and signal to noise ratio. Many parameters have a strong effect on these image properties, particularly the number of spokes used which impacts voxel size. The present article develops an understanding of the trade-offs involved and how to choose optimal (or at least reasonable) parameter values. This has a practical role in designing clinical protocols for imaging sodium.
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http://dx.doi.org/10.1016/j.mri.2021.07.004DOI Listing
July 2021

Detection of cerebral reorganization associated with degenerative cervical myelopathy using diffusion spectral imaging (DSI).

J Clin Neurosci 2021 Apr 5;86:164-173. Epub 2021 Feb 5.

Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Neuroscience Interdisciplinary Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Dept. of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Degenerative Cervical Myelopathy (DCM) is a spinal cord disorder that causes significant physical disabilities in older patients. While most DCM research focuses on the spinal cord, widespread reorganization of the brain may occur to compensate for functional impairment. This observational study used diffusion spectrum imaging (DSI) to examine reorganization of cerebral white matter associated with neurological impairment as measured by the modified Japanese Orthopedic Association (mJOA), and severity of neck disability as measured by the Neck Disability Index (NDI) score. A total of 47 patients were included in the cervical spondylosis (CS) cohort: 38 patients with DCM (mean mJOA = 14.6, and mean NDI = 12.0), and 9 neurologically asymptomatic patients with spinal cord compression (mJOA = 18, and mean NDI = 7.0). 28 healthy volunteers (HCs) served as the control group. Lower generalized fractional anisotropy (GFA) was observed throughout much of the brain in patients compared to HCs (p < 0.05). Fiber pathways associated with somatosensory functions, such as the corpus callosum and corona radiata, showed increased quantitative anisotropy (QA) in patients compared to HCs. Correlation analyses further suggested that structural connectivity was enhanced to compensate for neurological dysfunction within sensorimotor regions, where fibers such as the posterior corona radiata had NQA values that were negatively associated with mJOA (p = 0.0020, R = 0.2935) and positively associated with NDI score (p = 0.0164, R = 0.1889). Altogether, these results suggest that DCM and neurologically asymptomatic spinal cord compression patients tend to have long-term reorganization within the brain, particularly in those regions responsible for the perception and integration of sensory information, motor regulation, and pain modulation.
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http://dx.doi.org/10.1016/j.jocn.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007933PMC
April 2021

Preferential tumor localization in relation to F-FDOPA uptake for lower-grade gliomas.

J Neurooncol 2021 May 11;152(3):573-582. Epub 2021 Mar 11.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd., Suite 615, Los Angeles, CA, 90024, USA.

Purpose: Although tumor localization and 3,4-dihydroxy-6-F-fluoro-L-phenylalanine (FDOPA) uptake may have an association, preferential tumor localization in relation to FDOPA uptake is yet to be investigated in lower-grade gliomas (LGGs). This study aimed to identify differences in the frequency of tumor localization between FDOPA hypometabolic and hypermetabolic LGGs using a probabilistic radiographic atlas.

Methods: Fifty-one patients with newly diagnosed LGG (WHO grade II, 29; III, 22; isocitrate dehydrogenase wild-type, 21; mutant 1p19q non-codeleted,16; mutant codeleted, 14) who underwent FDOPA positron emission tomography (PET) were retrospectively selected. Semiautomated tumor segmentation on FLAIR was performed. Patients with LGGs were separated into two groups (FDOPA hypometabolic and hypermetabolic LGGs) according to the normalized maximum standardized uptake value of FDOPA PET (a threshold of the uptake in the striatum) within the segmented regions. Spatial normalization procedures to build a 3D MRI-based atlas using each segmented region were validated by an analysis of differential involvement statistical mapping.

Results: Superimposition of regions of interest showed a high number of hypometabolic LGGs localized in the frontal lobe, while a high number of hypermetabolic LGGs was localized in the insula, putamen, and temporal lobe. The statistical mapping revealed that hypometabolic LGGs occurred more frequently in the superior frontal gyrus (close to the supplementary motor area), while hypermetabolic LGGs occurred more frequently in the insula.

Conclusion: Radiographic atlases revealed preferential frontal lobe localization for FDOPA hypometabolic LGGs, which may be associated with relatively early detection.
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http://dx.doi.org/10.1007/s11060-021-03730-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221401PMC
May 2021

A cross-sectional study of the epidemic situation on COVID-19 in Gansu Province, China - a big data analysis of the national health information platform.

BMC Infect Dis 2021 Feb 5;21(1):146. Epub 2021 Feb 5.

School of Public Health, Lanzhou University, Lanzhou, China.

Background: In December 2019, a pneumonia caused by SARS-CoV-2 emerged in Wuhan, China and has rapidly spread around the world since then. This study is to explore the patient characteristics and transmission chains of COVID-19 in the population of Gansu province, and support decision-making.

Methods: We collected data from Gansu Province National Health Information Platform. A cross-sectional study was conducted, including patients with COVID-19 confirmed between January 23 and February 6, 2020, and analyzed the gender and age of the patients. We also described the incubation period, consultation time and sources of infection in the cases, and calculated the secondary cases that occurred within Gansu for each imported case.

Results: We found thirty-six (53.7%) of the patients were women and thirty-one (46.3%) men, and the median ages were 40 (IQR 31-53) years. Twenty-eight (41.8%) of the 67 cases had a history of direct exposure in Wuhan. Twenty-five (52.2%) cases came from ten families, and we found no clear reports of modes of transmission other than family clusters. The largest number of secondary cases linked to a single source was nine.

Conclusion: More women than men were diagnosed with COVID-19 in Gansu Province. Although the age range of confirmed cases of COVID-19 in Gansu Province covered almost all age groups, most patients with confirmed COVID-19 tend to be middle aged persons. The most common suspected mode of transmission was through family cluster. Gansu and other settings worldwide should continue to strengthen the utilization of big data in epidemic control.
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http://dx.doi.org/10.1186/s12879-020-05743-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863032PMC
February 2021

A physical phantom for amine chemical exchange saturation transfer (CEST) MRI.

MAGMA 2021 Jan 23. Epub 2021 Jan 23.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, CA, USA.

Objective: To develop a robust amine chemical exchange saturation transfer (CEST) physical phantom, validate the temporal stability, and create a supporting software for automatic image processing and quality assurance.

Materials And Methods: The phantom was designed as an assembled laser-cut acrylic rack and 18 vials of phantom solutions, prepared with different pHs, glycine concentrations, and gadolinium concentrations. We evaluated glycine concentrations using ultraviolet absorbance for 70 days and measured the pH, relaxation rates, and CEST contrast for 94 days after preparation. We used Spearman's correlation to determine if glycine degraded over time. Linear regression and Bland-Altman analysis were performed between baseline and follow-up measurements of pH and MRI properties.

Results: No degradation of glycine was observed (p > 0.05). The pH and MRI measurements stayed stable for 3 months and showed high consistency across time points (R = 1.00 for pH, R, R, and CEST contrast), which was further validated by the Bland-Altman plots. Examples of automatically generated reports are provided.

Discussion: We designed a physical phantom for amine CEST-MRI, which is easy to assemble and transfer, holds 18 different solutions, and has excellent short-term chemical and MRI stability. We believe this robust phantom will facilitate the development of novel sequences and cross-scanners validations.
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http://dx.doi.org/10.1007/s10334-020-00902-zDOI Listing
January 2021

Minimizing echo and repetition times in magnetic resonance imaging using a double half-echo k-space acquisition and low-rank reconstruction.

NMR Biomed 2021 04 9;34(4):e4458. Epub 2020 Dec 9.

Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Sampling k-space asymmetrically (ie, partial Fourier sampling) in the readout direction is a common way to reduce the echo time (TE) during magnetic resonance image acquisitions. This technique requires overlap around the center of k-space to provide a calibration region for reconstruction, which limits the minimum fractional echo to ~60% before artifacts are observed. The present study describes a method for reconstructing images from exact half echoes using two separate acquisitions with reversed readout polarity, effectively providing a full line of k-space without additional data around central k-space. This approach can benefit sequences or applications that prioritize short TE, short inter-echo spacing or short repetition time. An example of the latter is demonstrated to reduce banding artifacts in balanced steady-state free precession.
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http://dx.doi.org/10.1002/nbm.4458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935763PMC
April 2021

Self-Sealing Carbon Patterns by One-Step Direct Laser Writing and Their Use in Multifunctional Wearable Sensors.

ACS Appl Mater Interfaces 2020 Nov 31;12(45):50600-50609. Epub 2020 Oct 31.

College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Soochow 215123, P. R. China.

A combined photothermal simulation and experimental study leads to a novel internal reflection-assisted direct laser writing carbonization method (IR-DLWc), which enables in situ fabrication of carbon features/patterns that are self-sealed in the interior of a thin polyimide (PI) film in one step without additional packaging procedures. With this new method, carbon line patterns that are fully contained in a 50 μm PI film are fabricated, characterized, and evaluated for their electrical and piezoresistive performance. The self-sealing character of the carbon features created by IR-DLWc imparts them unprecedented mechanical stability/robustness as compared to those fabricated by the conventional DLWc method. Upon applying a double-writing scheme and strain-engineering treatment, the IR-DLWc-created carbon lines show significantly improved piezoresistive sensitivity with a gauge factor evaluated to be 428 in tension and 107 in compression. The high piezoresistive sensitivity, excellent dynamic response, reasonably good durability, self-sealing character, and compliant nature of the IR-DLWc generated carbon patterns make them suitable for a variety of wearable sensing applications. In this work, we demonstrated their use as a tactile sensor for sensing contact force; a functional bandage for monitoring physiological activities like swallowing, pulsing, and breathing; and a glove sensing system for finger gesture recognition.
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http://dx.doi.org/10.1021/acsami.0c14949DOI Listing
November 2020

Relative oxygen extraction fraction (rOEF) MR imaging reveals higher hypoxia in human epidermal growth factor receptor (EGFR) amplified compared with non-amplified gliomas.

Neuroradiology 2021 Jun 26;63(6):857-868. Epub 2020 Oct 26.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Purpose: Epidermal growth factor receptor (EGFR) amplification promotes gliomagenesis and is linked to lack of oxygen within the tumor microenvironment. Using hypoxia-sensitive spin-and-gradient echo echo-planar imaging and perfusion MRI, we investigated the influence of EGFR amplification on tissue oxygen availability and utilization in human gliomas.

Methods: This study included 72 histologically confirmed EGFR-amplified and non-amplified glioma patients. Reversible transverse relaxation rate (R'), relative cerebral blood volume (rCBV), and relative oxygen extraction fraction (rOEF) were calculated for the contrast-enhancing and non-enhancing tumor regions. Using Student t test or Wilcoxon rank-sum test, median R', rCBV, and rOEF were compared between EGFR-amplified and non-amplified gliomas. ROC analysis was performed to assess the ability of imaging characteristics to discriminate EGFR amplification status. Overall survival (OS) was determined using univariate and multivariate cox models. Kaplan-Meier survival curves were plotted and compared using the log-rank test.

Results: EGFR amplified gliomas exhibited significantly higher median R' and rOEF than non-amplified gliomas. ROC analysis suggested that R' (AUC = 0.7190; P = 0.0048) and rOEF (AUC = 0.6959; P = 0.0156) could separate EGFR status. Patients with EGFR-amplified gliomas had a significantly shorter OS than non-amplified patients. Univariate cox regression analysis determined both R' and rOEF significantly influence OS. No significant difference was observed in rCBV between patient cohorts nor was rCBV found to be an effective differentiator of EGFR status.

Conclusion: Imaging of tumor oxygen characteristics revealed EGFR-amplified gliomas to be more hypoxic and contribute to shorter patient survival than EGFR non-amplified gliomas.
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http://dx.doi.org/10.1007/s00234-020-02585-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071834PMC
June 2021

Maximum Uptake and Hypermetabolic Volume of 18F-FDOPA PET Estimate Molecular Status and Overall Survival in Low-Grade Gliomas: A PET and MRI Study.

Clin Nucl Med 2020 Dec;45(12):e505-e511

Department of Radiological Science, David Geffen School of Medicine.

Purpose: We evaluated F-FDOPA PET and MRI characteristics in association with the molecular status and overall survival (OS) in a large number of low-grade gliomas (LGGs).

Methods: Eighty-six patients who underwent F-FDOPA PET and MRI and were diagnosed with new or recurrent LGGs were retrospectively evaluated with respect to their isocitrate dehydrogenase (IDH) and 1p19q status (10 IDH wild type, 57 mutant, 19 unknown; 1p19q status in IDH mutant: 20 noncodeleted, 37 codeleted). After segmentation of the hyperintense area on fluid-attenuated inversion recovery image (FLAIRROI), the following were calculated: normalized SUVmax (nSUVmax) of F-FDOPA relative to the striatum, F-FDOPA hypermetabolic volume (tumor-to-striatum ratios >1), FLAIRROI volume, relative cerebral blood volume, and apparent diffusion coefficient within FLAIRROI. Receiver operating characteristic curve and Cox regression analyses were performed.

Results: PET and MRI metrics combined with age predicted the IDH mutation and 1p19q codeletion statuses with sensitivities of 73% and 76% and specificities of 100% and 94%, respectively. Significant correlations were found between OS and the IDH mutation status (hazard ratio [HR] = 4.939), nSUVmax (HR = 2.827), F-FDOPA hypermetabolic volume (HR = 1.048), and FLAIRROI volume (HR = 1.006). The nSUVmax (HR = 151.6) for newly diagnosed LGGs and the F-FDOPA hypermetabolic volume (HR = 1.038) for recurrent LGGs demonstrated significant association with OS.

Conclusions: Combining F-FDOPA PET and MRI with age proved useful for predicting the molecular status in patients with LGGs, whereas the nSUVmax and F-FDOPA hypermetabolic volume may be useful for prognostication.
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http://dx.doi.org/10.1097/RLU.0000000000003318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950323PMC
December 2020

Influence of phosphate concentration on amine, amide, and hydroxyl CEST contrast.

Magn Reson Med 2021 02 16;85(2):1062-1078. Epub 2020 Sep 16.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California, USA.

Purpose: To evaluate the influence of phosphate on amine, amide, and hydroxyl CEST contrast using Bloch-McConnell simulations applied to physical phantom data.

Methods: Phantom solutions of 4 representative metabolites with exchangeable protons-glycine (α-amine protons), Cr (η-amine protons), egg white protein (amide protons), and glucose (hydroxyl protons)-were prepared at different pH levels (5.6 to 8.9) and phosphate concentrations (5 to 80 mM). CEST images of the phantom were collected with CEST-EPI sequence at 3 tesla. The CEST data were then fitted to full Bloch-McConnell equation simulations to estimate the exchange rate constants. With the fitted parameters, simulations were performed to evaluate the intracellular and extracellular contributions of CEST signals in normal brain tissue and brain tumors, as well as in dynamic glucose-enhanced experiments.

Results: The exchange rates of α-amine and hydroxyl protons were found to be highly dependent on both pH and phosphate concentrations, whereas the exchange rates of η-amine and amide protons were pH-dependent, albeit not catalyzed by phosphate. With phosphate being predominantly intracellular, CEST contrast of α-amine exhibited a higher sensitivity to changes in the extracellular microenvironment. Simulations of dynamic glucose-enhanced signals demonstrated that the contrast between normal and tumor tissue was mostly due to the extracellular CEST effect.

Conclusion: The proton exchange rates in some metabolites can be greatly catalyzed by the presence of phosphate at physiological concentrations, which substantially alters the CEST contrast. Catalytic agents should be considered as confounding factors in future CEST-MRI research. This new dimension may also benefit the development of novel phosphate-sensitive imaging methods.
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http://dx.doi.org/10.1002/mrm.28481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258865PMC
February 2021

Multiparametric MR-PET measurements in hypermetabolic regions reflect differences in molecular status and tumor grade in treatment-naïve diffuse gliomas.

J Neurooncol 2020 Sep 14;149(2):337-346. Epub 2020 Sep 14.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd, Suite 615, Los Angeles, CA, 90024, USA.

Purpose: To assess whether hypermetabolically-defined regions of interest (ROIs) on 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) could be used to evaluate physiological features and whether there are measurable differences between molecular subtypes and tumor grades.

Methods: Sixty-eight treatment-naïve glioma patients who underwent FDOPA PET and magnetic resonance imaging (MRI) were retrospectively included. Fluid-attenuated inversion recovery hyperintense regions (FLAIR) were segmented. FDOPA hypermetabolic regions (FDOPA, tumor-to-striatum ratios > 1) within FLAIR were extracted. Normalized maximum standardized uptake value (nSUV), volume of each ROI, and median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) within FLAIR or FDOPA were calculated. Imaging metrics were compared using Students t or Mann-Whitney U tests. Area under the curve (AUC) of receiver-operating characteristic curves were used to determine whether imaging metrics within FLAIR or FDOPA can discriminate different molecular statuses or grades.

Results: Using either FLAIR or FDOPA, the nSUV and rCBV were significantly higher and the ADC was lower in isocitrate dehydrogenase (IDH) wild-type than mutant gliomas, and in higher-grade gliomas (HGGs) than lower-grade gliomas (LGGs). The FDOPA volume was significantly higher in 1p19q codeleted than non-codeleted gliomas, and in HGGs than LGGs. Although not significant, imaging metrics extracted by FDOPA discriminated molecular status and tumor grade more accurately than those extracted by FLAIR (AUC of IDH status, 0.87 vs. 0.82; 1p19q status, 0.78 vs. 0.73; grade, 0.87 vs. 0.76).

Conclusion: FDOPA hypermetabolic ROI may extract useful imaging features of gliomas, which can illuminate biological differences between different molecular status or tumor grades.
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http://dx.doi.org/10.1007/s11060-020-03613-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682113PMC
September 2020

Decorin expression is associated with predictive diffusion MR phenotypes of anti-VEGF efficacy in glioblastoma.

Sci Rep 2020 09 9;10(1):14819. Epub 2020 Sep 9.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers (CVIB), Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd, Suite 615, Los Angeles, CA, 90024, USA.

Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADC values, the average ADC in the lower distribution using a double Gaussian mixed model. ADC values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADC tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADC levels and DCN protein expression between tumors (Pearson R = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADC on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.
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http://dx.doi.org/10.1038/s41598-020-71799-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481206PMC
September 2020

Human IDH mutant 1p/19q co-deleted gliomas have low tumor acidity as evidenced by molecular MRI and PET: a retrospective study.

Sci Rep 2020 07 17;10(1):11922. Epub 2020 Jul 17.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, 924 Westwood Blvd., Suite 615, Los Angeles, CA, 90024, USA.

Co-deletion of 1p/19q is a hallmark of oligodendroglioma and predicts better survival. However, little is understood about its metabolic characteristics. In this study, we aimed to explore the extracellular acidity of WHO grade II and III gliomas associated with 1p/19q co-deletion. We included 76 glioma patients who received amine chemical exchange saturation transfer (CEST) imaging at 3 T. Magnetic transfer ratio asymmetry (MTR) at 3.0 ppm was used as the pH-sensitive CEST biomarker, with higher MTR indicating lower pH. To control for the confounder factors, T relaxometry and L-6-F-fluoro-3,4-dihydroxyphenylalnine (F-FDOPA) PET data were collected in a subset of patients. We found a significantly lower MTR in 1p/19q co-deleted gliomas (co-deleted, 1.17% ± 0.32%; non-co-deleted, 1.72% ± 0.41%, P = 1.13 × 10), while FDOPA (P = 0.92) and T (P = 0.61) were not significantly affected. Receiver operating characteristic analysis confirmed that MTR could discriminate co-deletion status with an area under the curve of 0.85. In analysis of covariance, 1p/19q co-deletion status was the only significant contributor to the variability in MTR when controlling for age and FDOPA (P = 2.91 × 10) or T (P = 8.03 × 10). In conclusion, 1p/19q co-deleted gliomas were less acidic, which may be related to better prognosis. Amine CEST-MRI may serve as a non-invasive biomarker for identifying 1p/19q co-deletion status.
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http://dx.doi.org/10.1038/s41598-020-68733-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367867PMC
July 2020

Voxelwise and Patientwise Correlation of F-FDOPA PET, Relative Cerebral Blood Volume, and Apparent Diffusion Coefficient in Treatment-Naïve Diffuse Gliomas with Different Molecular Subtypes.

J Nucl Med 2021 03 9;62(3):319-325. Epub 2020 Jul 9.

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, UCLA, Los Angeles, California

Our purpose was to identify correlations between F-fluorodihydroxyphenylalanine (F-FDOPA) uptake and physiologic MRI, including relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC), in gliomas with different molecular subtypes and to evaluate their prognostic values. Sixty-eight treatment-naïve glioma patients who underwent F-FDOPA PET and physiologic MRI were retrospectively selected (36 with isocitrate dehydrogenase wild-type [IDH], 16 with mutant 1p/19q noncodeleted [IDH], and 16 with mutant codeleted [IDH]). Fluid-attenuated inversion recovery hyperintense areas were segmented and used as regions of interest. For voxelwise and patientwise analyses, Pearson correlation coefficients ( and ) between the normalized SUV (nSUV), rCBV, and ADC were evaluated. Cox regression analysis was performed to investigate the associations between overall survival and , maximum or median nSUV, median rCBV, or median ADC. For IDH and IDH gliomas, nSUV demonstrated significant positive correlations with rCBV ( = 0.25 and 0.31, respectively; = 0.50 and 0.70, respectively) and negative correlations with ADC ( = -0.19 and -0.19, respectively; = -0.58 and -0.61, respectively) in both voxelwise and patientwise analyses. IDH gliomas demonstrated a significant positive correlation between nSUV and ADC only in voxelwise analysis ( = 0.18). In Cox regression analysis, between nSUV and rCBV (hazard ratio, 28.82) or ADC (hazard ratio, 0.085) had significant associations with overall survival for only IDH gliomas. IDH gliomas showed distinctive patterns of correlations between amino acid PET and physiologic MRI. Stronger correlations between nSUV and rCBV or ADC may result in a worse prognosis for IDH gliomas.
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http://dx.doi.org/10.2967/jnumed.120.247411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049346PMC
March 2021

Curcumin-enhanced antitumor effects of sorafenib via regulating the metabolism and tumor microenvironment.

Food Funct 2020 Jul;11(7):6422-6432

State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China.

Curcumin, the main active ingredient of turmeric, is widely used as a kind of food additive and also displays a range of pharmacological activities, such as anti-inflammation, anti-tumor, liver and kidney protection, and so forth. Sorafenib was the first targeted agent against hepatocellular carcinoma (HCC), whose intolerance is related to the promotion of lipid synthesis and epithelial-to-mesenchymal transition (EMT) formation. In this study, biochemical analysis, immune cells composition, the tumor microenvironment, metabolomics, and relative metabolic enzymes and transporters were detected in H22-bearing mice treated with curcumin combined with sorafenib vs. control groups. It was found that curcumin protected against liver cancer progression through reducing the level of alpha fetoprotein in liver tissues, increasing the number of immune cells, like NK cells, inhibiting EMT via the regulation of IL-6/JAK/STAT3 and IL-1β/NF-κB pathways, suppressing anaerobic glycolysis through the inhibition of LDH and HIF-1α, and decreasing the lipid synthesis via the downregulation of FASN, and upregulated the serum HDL-C and mRNA levels of apoA1 in the sorafenib-treated mice. Furthermore, curcumin regulation of the disorder of glycolipid metabolism and EMT was also based on the PI3K/AKT pathway. A docking study was performed and proved the strong affinity between curcumin and the proteins of STAT3, FASN, and AKT. All in all, this experiment provided evidence for the addition of curcumin in the diet to enhance the antitumor efficacy of sorafenib through activating immune function, downregulating EMT, and reversing disorders of the metabolism.
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http://dx.doi.org/10.1039/c9fo01901dDOI Listing
July 2020

Diffusion Magnetic Resonance Imaging Phenotypes Predict Overall Survival Benefit From Bevacizumab or Surgery in Recurrent Glioblastoma With Large Tumor Burden.

Neurosurgery 2020 10;87(5):931-938

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Background: Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated.

Objective: To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection.

Methods: A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor.

Results: In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P = .009, HR = 1.02; Surgical: P = .006, HR = 0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P = .049, HR = 0.44), but not the surgical cohort (P = .273, HR = 0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P = .036, HR = 0.43) but not in patients with high ADCL (P = .284, HR = 0.69).

Conclusion: Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab.
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http://dx.doi.org/10.1093/neuros/nyaa135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566341PMC
October 2020

Multiparametric MR-PET Imaging Predicts Pharmacokinetics and Clinical Response to GDC-0084 in Patients with Recurrent High-Grade Glioma.

Clin Cancer Res 2020 07 8;26(13):3135-3144. Epub 2020 Apr 8.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: GDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. Because these two targets alter tumor vascularity and metabolism, respectively, we hypothesized multiparametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas.

Patients And Methods: Multiparametric advanced MR-PET imaging was performed to evaluate physiologic response in a first-in-man, multicenter, phase I, dose-escalation study of GDC-0084 (NCT01547546) in 47 patients with recurrent malignant glioma.

Results: Measured maximum concentration ( ) was associated with a decrease in enhancing tumor volume ( = 0.0287) and an increase in fractional anisotropy (FA; = 0.0418). Posttreatment tumor volume, F-FDG uptake, K, and relative cerebral blood volume (rCBV) were all correlated with . A linear combination of change in F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, K, v, and rCBV was able to estimate both ( = 0.4113; < 0.0001) and drug exposure (AUC; = 0.3481; < 0.0001). Using this composite multiparametric MR-PET imaging response biomarker to predict PK, patients with an estimated > 0.1 μmol/L and AUC > 1.25 μmol/L*hour demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure ( = 0.0039 and = 0.0296, respectively).

Conclusions: Results from this study suggest composite biomarkers created from multiparametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204664PMC
July 2020

Rate of change in maximum F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas.

J Neurooncol 2020 Mar 24;147(1):135-145. Epub 2020 Jan 24.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Purpose: To examine whether the rate of change in maximum F-FDOPA PET uptake and the rate of change in non-enhancing tumor volume could predict malignant transformation and residual overall survival (OS) in low grade glioma (LGG) patients who received serial F-FDOPA PET and MRI scans.

Methods: 27 LGG patients with ≥ 2 F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized F-FDOPA specific uptake value (nSUV/month), were compared between histological and molecular subtypes. General linear models (GLMs) were used to integrate clinical information with MR-PET measurements to predict malignant transformation. Cox univariate and multivariable regression analyses were performed to identify imaging and clinical risk factors related to OS.

Results: A GLM using patient age, treatment, the rate of change in FLAIR and F-FDOPA nSUV could predict malignant transformation with > 67% sensitivity and specificity (AUC = 0.7556, P = 0.0248). A significant association was observed between OS and continuous rates of change in PET uptake (HR = 1.0212, P = 0.0034). Cox multivariable analysis confirmed that continuous measures of the rate of change in PET uptake was an independent predictor of OS (HR = 1.0242, P = 0.0033); however, stratification of patients based on increasing or decreasing rate of change in FLAIR (HR = 2.220, P = 0.025), PET uptake (HR = 2.148, P = 0.0311), or both FLAIR and PET (HR = 2.354, P = 0.0135) predicted OS.

Conclusions: The change in maximum normalized F-FDOPA PET uptake, with or without clinical information and rate of change in tumor volume, may be useful for predicting the risk of malignant transformation and estimating residual survival in patients with LGG.
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http://dx.doi.org/10.1007/s11060-020-03407-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080591PMC
March 2020

Efficient Deep-Blue Fluorescent OLEDs with a High Exciton Utilization Efficiency from a Fully Twisted Phenanthroimidazole-Anthracene Emitter.

ACS Appl Mater Interfaces 2019 Aug 15;11(34):31139-31146. Epub 2019 Aug 15.

Institute of Polymer Optoelectronic Materials and Devices, State Key Laboratory of Luminescent Materials and Devices , South China University of Technology , Guangzhou 510640 , P. R. China.

A novel, efficient, deep-blue fluorescent emitter mPAC, with a meta-connected donor-acceptor structure containing phenanthroimidazole (PPI) as the donor and phenylcarbazole-substituted anthracene (An-CzP) as the acceptor, was designed and synthesized. The meta-linkage provided a highly twisted molecular conformation, which efficiently interrupts the intramolecular π-conjugation, resulting in a deep-blue emission. The optimized nondoped device based on mPAC displayed a deep-blue emission with a narrow full width at half-maximum of 56 nm and Commission Internationale de L'Eclairage coordinates of (0.16, 0.09). The maximum external quantum efficiency (EQE) is 6.76%, corresponding to a high exciton utilization efficiency (EUE) of 59.3-88.9%. Experimental results and theoretical analysis indicated that the high EUE is mainly ascribed to the reverse intersystem crossing (RISC) from T to S, a "hot exciton" path in which the large T-T energy gap (1.45 eV) and small T-S energy difference (0.18 eV, T > S) hamper the internal crossing from T to T and facilitate the RISC process. For the hot exciton path, the T state can be feasibly arranged to a high energy level, forming a thermal equilibrium with S, even slightly higher than the deep-blue S to realize an exergonic RISC process, which is usually difficult for the thermally activated delayed fluorescence emitters.
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http://dx.doi.org/10.1021/acsami.9b10823DOI Listing
August 2019

Metabolic characterization of human IDH mutant and wild type gliomas using simultaneous pH- and oxygen-sensitive molecular MRI.

Neuro Oncol 2019 09;21(9):1184-1196

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, University of California Los Angeles, Los Angeles, California.

Background: Isocitrate dehydrogenase 1 (IDH1) mutant gliomas are thought to have distinct metabolic characteristics, including a blunted response to hypoxia and lower glycolytic flux. We hypothesized that non-invasive quantification of abnormal metabolic behavior in human IDH1 mutant gliomas could be performed using a new pH- and oxygen-sensitive molecular MRI technique.

Methods: Simultaneous pH- and oxygen-sensitive MRI was obtained at 3T using amine CEST-SAGE-EPI. The pH-dependent measure of the magnetization transfer ratio asymmetry (MTRasym) at 3 ppm and oxygen-sensitive measure of R2' were quantified in 90 patients with gliomas. Additionally, stereotactic, image-guided biopsies were performed in 20 patients for a total of 52 samples. The association between imaging measurements and hypoxia-inducible factor 1 alpha (HIF1α) expression was identified using Pearson correlation analysis.

Results: IDH1 mutant gliomas exhibited significantly lower MTRasym at 3 ppm, R2', and MTRasymxR2' (P = 0.007, P = 0.003, and P = 0.001, respectively). MTRasymxR2' could identify IDH1 mutant gliomas with a high sensitivity (81.0%) and specificity (81.3%). HIF1α was positively correlated with MTRasym at 3 ppm, R2' and MTRasymxR2' in IDH1 wild type (r = 0.610, P = 0.003; r = 0.667, P = 0.008; r = 0.635, P = 0.006), but only MTRasymxR2' in IDH1 mutant gliomas (r = 0.727, P = 0.039).

Conclusions: IDH1 mutant gliomas have distinct metabolic and microenvironment characteristics compared with wild type gliomas. An imaging biomarker combining tumor acidity and hypoxia (MTRasymxR2') can differentiate IDH1 mutation status and is correlated with tumor acidity and hypoxia.
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http://dx.doi.org/10.1093/neuonc/noz078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594567PMC
September 2019

UVGD 1.0: a gene-centric database bridging ultraviolet radiation and molecular biology effects in organisms.

Int J Radiat Biol 2019 08 13;95(8):1172-1177. Epub 2019 May 13.

a State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences-Beijing (PHOENIX Center), Beijing Institute of Lifeomics , Beijing , China.

Exposing to ultraviolet for a certain time will trigger some significant molecular biology effects in an organism. In the past few decades, varied ultraviolet-associated biological effects as well as their related genes, have been discovered under biologists' efforts. However, information about ultraviolet-related genes is dispersed in thousands of scientific papers, and there is still no study emphasizing on the systematic collection of ultraviolet-related genes. We collected ultraviolet-related genes and built this gene-centric database UVGD based on literature mining and manual curation. Literature mining was based on the ultraviolet-related abstracts downloaded from PubMed, and we obtained sentences in which ultraviolet keywords and genes co-occur at single-sentence level by using bio-entity recognizer. After that, manual curation was implemented in order to identify whether the genes are related to ultraviolet or not. We built the ultraviolet-related knowledge base UVGD 1.0 (URL: http://biokb.ncpsb.org/UVGD/ ), which contains 663 ultraviolet-related genes, together with 17 associated biological processes, 117 associated phenotypes, and 2628 MeSH terms. UVGD is helpful to understand the ultraviolet-related biological processes in organisms and we believe it would be useful for biologists to study the responding mechanisms to ultraviolet.
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http://dx.doi.org/10.1080/09553002.2019.1609127DOI Listing
August 2019

Probabilistic independent component analysis of dynamic susceptibility contrast perfusion MRI in metastatic brain tumors.

Cancer Imaging 2019 Mar 18;19(1):14. Epub 2019 Mar 18.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, CA, USA.

Purpose: To identify clinically relevant magnetic resonance imaging (MRI) features of different types of metastatic brain lesions, including standard anatomical, diffusion weighted imaging (DWI) and dynamic susceptibility contrast (DSC) perfusion MRI.

Methods: MRI imaging was retrospectively assessed on one hundred and fourteen (N = 114) brain metastases including breast (n = 27), non-small cell lung cancer (NSCLC, n = 43) and 'other' primary tumors (n = 44). Based on 114 patient's MRI scans, a total of 346 individual contrast enhancing tumors were manually segmented. In addition to tumor volume, apparent diffusion coefficients (ADC) and relative cerebral blood volume (rCBV) measurements, an independent component analysis (ICA) was performed with raw DSC data in order to assess arterio-venous components and the volume of overlap (AVOL) relative to tumor volume, as well as time to peak (TTP) of T* signal from each component.

Results: Results suggests non-breast or non-NSCLC ('other') tumors had higher volume compare to breast and NSCLC patients (p = 0.0056 and p = 0.0003, respectively). No differences in median ADC or rCBV were observed across tumor types; however, breast and NSCLC tumors had a significantly higher "arterial" proportion of the tumor volume as indicated by ICA (p = 0.0062 and p = 0.0018, respectively), while a higher "venous" proportion were prominent in breast tumors compared with NSCLC (p = 0.0027) and 'other' lesions (p = 0.0011). The AVOL component was positively related to rCBV in all groups, but no correlation was found for arterial and venous components with respect to rCBV values. Median time to peak of arterial and venous components were 8.4 s and 12.6 s, respectively (p < 0.0001). No difference was found in arterial or venous TTP across groups.

Conclusions: Advanced ICA-derived component analysis demonstrates perfusion differences between metastatic brain tumor types that were not observable with classical ADC and rCBV measurements. These results highlight the complex relationship between brain tumor vasculature characteristics and the site of primary tumor diagnosis.
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http://dx.doi.org/10.1186/s40644-019-0201-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423873PMC
March 2019

pH-weighted molecular MRI in human traumatic brain injury (TBI) using amine proton chemical exchange saturation transfer echoplanar imaging (CEST EPI).

Neuroimage Clin 2019 25;22:101736. Epub 2019 Feb 25.

Dept. of Neurosurgery, UCLA Brain Injury Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Cerebral acidosis is a consequence of secondary injury mechanisms following traumatic brain injury (TBI), including excitotoxicity and ischemia, with potentially significant clinical implications. However, there remains an unmet clinical need for technology for non-invasive, high resolution pH imaging of human TBI for studying metabolic changes following injury. The current study examined 17 patients with TBI and 20 healthy controls using amine chemical exchange saturation transfer echoplanar imaging (CEST EPI), a novel pH-weighted molecular MR imaging technique, on a clinical 3T MR scanner. Results showed significantly elevated pH-weighted image contrast (MTR at 3 ppm) in areas of T2 hyperintensity or edema (P < 0.0001), and a strong negative correlation with Glasgow Coma Scale (GCS) at the time of the MRI exam (R = 0.4777, P = 0.0021), Glasgow Outcome Scale - Extended (GOSE) at 6 months from injury (R = 0.5334, P = 0.0107), and a non-linear correlation with the time from injury to MRI exam (R = 0.6317, P = 0.0004). This evidence suggests clinical feasibility and potential value of pH-weighted amine CEST EPI as a high-resolution imaging tool for identifying tissue most at risk for long-term damage due to cerebral acidosis.
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http://dx.doi.org/10.1016/j.nicl.2019.101736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396390PMC
December 2019

Validation of vessel size imaging (VSI) in high-grade human gliomas using magnetic resonance imaging, image-guided biopsies, and quantitative immunohistochemistry.

Sci Rep 2019 02 26;9(1):2846. Epub 2019 Feb 26.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

To evaluate the association between a vessel size index (VSI) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSI in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSI were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSI = 13.67 μm and VSI = 12.60 μm, with slight overestimation of VSI in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSI and VSI (r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber.
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http://dx.doi.org/10.1038/s41598-018-37564-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391482PMC
February 2019

pH-weighted amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) as a potential early biomarker for bevacizumab failure in recurrent glioblastoma.

J Neurooncol 2019 May 26;142(3):587-595. Epub 2019 Feb 26.

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, CA, USA.

Purpose: The objective of the current study was to explore the efficacy of using pH-weighted amine CEST-EPI as a potential non-invasive imaging biomarker for treatment response and/or failure in recurrent GBM patients treated with bevacizumab.

Method: A total of 11 patients with recurrent GBM treated with bevacizumab were included in this prospective study. CEST-EPI, perfusion MRI, and standardized anatomic MRI were obtained in patients before and after bevacizumab administration. CEST-EPI measures of magnetization transfer ratio asymmetry (MTR) at 3 ppm were used for pH-weighted imaging contrast. Multiple measures were examined for their association with progression-free survival (PFS).

Result: Tumor acidity, measured with MTR at 3 ppm, was significantly reduced in both contrast enhancing and non-enhancing tumor after bevacizumab (p = 0.0002 and p < 0.00001, respectively). The reduction in tumor acidity in both contrast enhancing and non-enhancing tumor was linearly correlated with PFS (p = 0.044 and p = 0.00026, respectively). In 9 of the 11 patients, areas of residual acidity were localized to areas of tumor recurrence, typically around 2 months prior to radiographic progression. Univariate (p = 0.006) and multivariate Cox regression controlling for age (p = 0.009) both indicated that change in tumor acidity (ΔMTR at 3 ppm) was a significant predictor of PFS.

Conclusions: This pilot study suggests pH-weighted amine CEST MRI may have value as a non-invasive, early imaging biomarker for bevacizumab treatment response and failure. Early decreases MTR at 3.0 ppm in recurrent GBM after bevacizumab may be associated with better PFS. Residual or emerging regions of acidity may colocalize to the site of tumor recurrence.
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http://dx.doi.org/10.1007/s11060-019-03132-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482078PMC
May 2019

Improving B Correction for pH-Weighted Amine Proton Chemical Exchange Saturation Transfer (CEST) Imaging by Use of k-Means Clustering and Lorentzian Estimation.

Tomography 2018 Sep;4(3):123-137

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.

Amine chemical exchange saturation transfer (CEST) echoplanar imaging (EPI) provides unique pH and amino acid MRI contrast, enabling sensitive detection of altered microenvironment properties in various diseases. However, CEST contrast is sensitive to static magnetic field (B) inhomogeneities. Here we propose 2 new B correction algorithms for use in correcting pH-weighted amine CEST EPI based on k-means clustering and Lorentzian fitting of CEST data: the iterative downsampling estimation using Lorentzian fitting and the 2-stage Lorentzian estimation with 4D polynomial fitting. Higher quality images of asymmetric magnetization transfer ratio (MTR) at 3.0 ppm could be obtained with the proposed algorithms than with the existing B correction methods. In particular, the proposed methods are shown to improve the intertissue consistency, interpatient consistency, and tumor region signal-to-noise ratio of MTR at 3.0 ppm images, with nonexcessive computation time.
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http://dx.doi.org/10.18383/j.tom.2018.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173788PMC
September 2018

Revealing the metabolic characteristics of human embryonic stem cells by genome-scale metabolic modeling.

FEBS Lett 2018 11 2;592(22):3670-3682. Epub 2018 Nov 2.

School of Life Sciences, Tsinghua University, Beijing, China.

Embryonic stem cells (ESCs) are characterized by a dual capacity, self-renewal and pluripotency, which can be regulated by metabolism. A better understanding of ESC metabolism and regulatory mechanisms is pivotal for research into development, ageing, and cancer treatment. However, a systematic and comprehensive delineation of human ESC metabolism is still lacking. Here, we reconstructed the first genome-scale metabolic model (GEM) of human ESCs (hESCs). By GEM simulation and analyses, hESC global metabolic characteristics including essential metabolites and network motifs were identified. Potential metabolic subsystems responsible for self-renewal and pluripotency were also identified by analyses and experiments. This first GEM of hESCs provides a novel view and resource for stem cell metabolism research and will contribute to the elucidation of their metabolic characteristics.
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http://dx.doi.org/10.1002/1873-3468.13255DOI Listing
November 2018

Combinatorial treatment of Rhizoma Paridis saponins and sorafenib overcomes the intolerance of sorafenib.

J Steroid Biochem Mol Biol 2018 10 19;183:159-166. Epub 2018 Jun 19.

Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China. Electronic address:

Sorafenib, as a multi-kinase inhibitor, was the first FDA-approved anti- hepatocellular carcinoma (HCC) drug. Rhizoma Paridis saponins (RPS) as natural products have shown antitumor activity through regulation of glycolytic and lipid metabolism which was regarded as the side effect limited the utility of sorafenib. In this research, we tried to use metabolomics to verify the probability of combinatorial treatment of RPS and Sorafenib. As a result, Sorafenib + RPS increased the antitumor effect of sorafenib and RPS in H22 mice. They mitigated the change of liver weight and the increasing levels of AST and ALT in serum, and AFP and MDA in liver tissues, which indicated their liver protective activity. They also up-regulated the activity of NOX and SDH, concentration of ATP, and down-regulated the mRNA and protein levels of HIF-1a and concentration of lactate, which suggested they protected against mitochondria damage and inhibited anaerobic glycolysis. Meanwhile, the combination group remarkably down-regulated the concentration of octadecanoic acid and hexadecanoic acid in serum, and tetradecanoic acid in liver tissues compared with model group (p < 0.05). Relative regulation mechanism included their decreasing mRNA levels of FASN, CPT1, GLUT1, Myc, Akt, mTOR and LDHA, and increasing the protein expression of p53 in tumor and liver tissues (p < 0.05). Furthermore, similar influence can be observed in protein levels of CPT1A, p-PI3K, p-mTOR and p53 in liver tissues and FASN in serum. All of that provided possibility to overcome the intolerance of sorafenib by drug compatibility through protection against mitochondria damage, inhibition of anaerobic glycolysis and suppression of lipid synthesis based on PI3K/Akt/mTOR pathway.
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http://dx.doi.org/10.1016/j.jsbmb.2018.06.010DOI Listing
October 2018

F-FDOPA PET and MRI characteristics correlate with degree of malignancy and predict survival in treatment-naïve gliomas: a cross-sectional study.

J Neurooncol 2018 Sep 20;139(2):399-409. Epub 2018 Apr 20.

UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Introduction: To report the potential value of pre-operative F-FDOPA PET and anatomic MRI in diagnosis and prognosis of glioma patients.

Methods: Forty-five patients with a pathological diagnosis of glioma with pre-operative F-FDOPA PET and anatomic MRI were retrospectively examined. The volume of contrast enhancement and T2 hyperintensity on MRI images along with the ratio of maximum F-FDOPA SUV in tumor to normal tissue (T/N SUV) were measured and used to predict tumor grade, molecular status, and overall survival (OS).

Results: A significant correlation was observed between WHO grade and: the volume of contrast enhancement (r = 0.67), volume of T2 hyperintensity (r = 0.42), and F-FDOPA uptake (r = 0.60) (P < 0.01 for each correlation). The volume of contrast enhancement and F-FDOPA T/N SUV were significantly higher in glioblastoma (WHO IV) compared with lower grade gliomas (WHO I-III), as well as for high-grade gliomas (WHO III-IV) compared with low-grade gliomas (WHO I-II). Receiver-operator characteristic (ROC) analyses confirmed the volume of contrast enhancement and F-FDOPA T/N SUV could each differentiate patient groups. No significant differences in F-FDOPA uptake were observed by IDH or MGMT status. Multivariable Cox regression suggested age (HR 1.16, P = 0.0001) and continuous measures of F-FDOPA PET T/N SUV (HR 4.43, P = 0.016) were significant prognostic factors for OS in WHO I-IV gliomas.

Conclusions: Current findings suggest a potential role for the use of pre-operative F-FDOPA PET in suspected glioma. Increased F-FDOPA uptake may not only predict higher glioma grade, but also worse OS.
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http://dx.doi.org/10.1007/s11060-018-2877-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092195PMC
September 2018

Simultaneous pH-sensitive and oxygen-sensitive MRI of human gliomas at 3 T using multi-echo amine proton chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI).

Magn Reson Med 2018 11 6;80(5):1962-1978. Epub 2018 Apr 6.

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Purpose: To introduce a new pH-sensitive and oxygen-sensitive MRI technique using amine proton CEST echo spin-and-gradient echo (SAGE) EPI (CEST-SAGE-EPI).

Methods: pH-weighting was obtained using CEST estimations of magnetization transfer ratio asymmetry (MTR ) at 3 ppm, and oxygen-weighting was obtained using R2' measurements. Glutamine concentration, pH, and relaxation rates were varied in phantoms to validate simulations and estimate relaxation rates. The values of MTR and R2' in normal-appearing white matter, T hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas.

Results: Simulation and phantom results confirmed an increase in MTR with decreasing pH. The CEST-SAGE-EPI estimates of R , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R  = 6.2 mM ·sec and R2* = 6.9 mM ·sec ). The CEST-SAGE-EPI and Carr-Purcell-Meiboom-Gill estimates of R (R  = 0.9943) and multi-echo gradient-echo estimates of R2* (R  = 0.9727) were highly correlated. T lesions had lower R2' and higher MTR compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTR , indicating high hypoxia and acidity.

Conclusion: The CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole-brain acquisition, in-line B correction, and simultaneous estimation of CEST effects, R , R2*, and R2' at 3 T.
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http://dx.doi.org/10.1002/mrm.27204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107417PMC
November 2018