Practical Application of Multivendor MRI-Based R2* Mapping for Liver Iron Quantification at 1.5 T and 3.0 T.

BACKGROUND: Recent multicenter, multivendor MRI-based R2* vs. liver iron concentration (LIC) calibrations (i.e., MCMV calibrations) may facilitate broad clinical dissemination of R2*-based LIC quantification. However, these calibrations are based on a centralized offline R2* reconstruction, and their applicability with vendor-provided R2* maps is unclear. PURPOSE: To determine R2* ranges of agreement between the centralized and three MRI vendors' R2* reconstructions. STUDY TYPE: Prospective. SUBJECTS: Two hundred and seven subjects (mean age 37.6 ± 19.6 years; 117 male) with known or suspected iron overload from four academic medical centers. FIELD STRENGTH/SEQUENCE: Standardized multiecho spoiled gradient echo sequence at 1.5 T and 3.0 T for R2* mapping and a multiple spin-echo sequence at 1.5 T for LIC quantification. MRI vendors: GE Healthcare, Philips Healthcare, and Siemens Healthineers. ASSESSMENT: R2* maps were generated using both the centralized and vendor reconstructions, and ranges of agreement were determined. R2*-LIC linear calibrations were determined for each site, field strength, and reconstruction and compared with the MCMV calibrations. STATISTICAL TESTS: Bland-Altman analysis to determine ranges of agreement. Linear regression, analysis of covariance F tests, and Tukey's multiple comparison testing to assess reproducibility of calibrations across sites and vendors. A P value <0.05 was considered significant. RESULTS: The upper limits of R2* ranges of agreement were approximately 500, 375, and 330 s-1 for GE, Philips, and Siemens reconstructions, respectively, at 1.5 T and approximately 700 and 800 s-1 for GE and Philips, respectively, at 3.0 T. Within the R2* ranges of agreement, vendor R2*-LIC calibrations demonstrated high reproducibility (no significant differences between slopes or intercepts; P ≥ 0.06) and agreed with the MCMV calibrations (overlapping 95% confidence intervals). DATA CONCLUSION: Based on the determined upper limits, R2* measurements obtained from vendor-provided R2* maps may be reliably and practically used to quantify LIC less than approximately 8-13 mg/g using the MCMV calibrations and similar acquisition parameters as this study. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Akkermansia muciniphila-derived pentadecanoic acid enhances oxaliplatin sensitivity in gastric cancer by modulating glycolysis.

Accumulating evidence has proved the close association between alterations in gut microbiota and resistance to chemotherapeutic drugs. However, the potential roles of gut microbiota in regulating oxaliplatin sensitivity in gastric cancer (GC) have not been investigated before. We first found that antibiotic treatment diminished the therapeutic efficacy of oxaliplatin in a GC mouse model. Importantly, this effect could be transmitted to germ-free mice via fecal microbiota transplantation, indicating a potential role of gut microbiota modulation in oxaliplatin efficacy. Further, metagenomics data showed that Akkermansia muciniphila (A. muciniphila) ranked first among the bacterial species with decreased relative abundances after antibiotic treatment. Metabolically active A. muciniphila promotes oxaliplatin efficacy. As shown by metabolomics analysis, the metabolic pattern of gut microbiota was disrupted with significantly downregulated levels of pentadecanoic acid (PEA), and the use of PEA significantly promoted oxaliplatin efficacy. Mechanistically, FUBP1 positively regulated aerobic glycolysis of GC cells to hinder the therapeutic efficacy of oxaliplatin. A. muciniphila-derived PEA functioned as an inhibitory factor of glycolysis by directly antagonizing the activity of FUBP1, which potentiated GC responses to oxaliplatin. Our research suggested a key role for intestinal A. muciniphila and its metabolite PEA in promoting oxaliplatin efficacy, thus providing a new perspective for probiotic and prebiotic intervention in GC patients during chemotherapy.

Multicenter Reproducibility of Liver Iron Quantification with 1.5-T and 3.0-T MRI.

Background MRI is a standard of care tool to measure liver iron concentration (LIC). Compared with regulatory-approved R2 MRI, R2* MRI has superior speed and is available in most MRI scanners; however, the cross-vendor reproducibility of R2*-based LIC estimation remains unknown. Purpose To evaluate the reproducibility of LIC via single-breath-hold R2* MRI at both 1.5 T and 3.0 T with use of a multicenter, multivendor study. Materials and Methods Four academic medical centers using MRI scanners from three different vendors (three 1.5-T scanners, one 2.89-T scanner, and two 3.0-T scanners) participated in this prospective cross-sectional study. Participants with known or suspected liver iron overload were recruited to undergo multiecho gradient-echo MRI for R2* mapping at 1.5 T and 3.0 T (2.89 T or 3.0 T) on the same day. R2* maps were reconstructed from the multiecho images and analyzed at a single center. Reference LIC measurements were obtained with a commercial R2 MRI method performed using standardized 1.5-T spin-echo imaging. R2*-versus-LIC calibrations were generated across centers and field strengths using linear regression and compared using F tests. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic performance of R2* MRI in the detection of clinically relevant LIC thresholds. Results A total of 207 participants (mean age, 38 years ± 20 [SD]; 117 male participants) were evaluated between March 2015 and September 2019. A linear relationship was confirmed between R2* and LIC. All calibrations within the same field strength were highly reproducible, showing no evidence of statistically significant center-specific differences (P > .43 across all comparisons). Calibrations for 1.5 T and 3.0 T were generated, as follows: for 1.5 T, LIC (in milligrams per gram [dry weight]) = -0.16 + 2.603 × 10-2 R2* (in seconds-1); for 2.89 T, LIC (in milligrams per gram) = -0.03 + 1.400 × 10-2 R2* (in seconds-1); for 3.0 T, LIC (in milligrams per gram) = -0.03 + 1.349 × 10-2 R2* (in seconds-1). Liver R2* had high diagnostic performance in the detection of clinically relevant LIC thresholds (area under the ROC curve, >0.98). Conclusion R2* MRI enabled accurate and reproducible quantification of liver iron overload over clinically relevant ranges of liver iron concentration (LIC). The data generated in this study provide the necessary calibrations for broad clinical dissemination of R2*-based LIC quantification. ClinicalTrials.gov registration no.: NCT02025543 © RSNA, 2022 Online supplemental material is available for this article.

Validation of liver quantitative susceptibility mapping across imaging parameters at 1.5 T and 3.0 T using SQUID susceptometry as reference.

PURPOSE: To validate QSM-based biomagnetic liver susceptometry (BLS) to measure liver iron overload at 1.5 T and 3.0 T using superconducting quantum interference devices (SQUID)-based BLS as reference. METHODS: Subjects with known or suspected iron overload were recruited for QSM-BLS at 1.5 T and 3.0 T using eight different protocols. SQUID-BLS was also obtained in each subject to provide susceptibility reference. A recent QSM method based on data-adaptive regularization was used to obtain susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps. Measurements of susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ were obtained in the right liver lobe. Linear mixed-effects analysis was used to estimate the contribution of specific acquisition parameters to QSM-BLS. Linear regression and Bland-Altman analyses were used to assess the relationship between QSM-BLS and SQUID-BLS/ R 2 * $$ {\mathrm{R}}_2^{\ast } $$ . RESULTS: Susceptibility maps showed high subjective quality for each acquisition protocol across different iron levels. High linear correlation was observed between QSM-BLS and SQUID-BLS at 1.5 T (r2 range, [0.82, 0.84]) and 3.0 T (r2 range, [0.77, 0.85]) across different acquisition protocols. QSM-BLS and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ were highly correlated at both field strengths (r2 range at 1.5 T, [0.94, 0.99]; 3.0 T, [0.93, 0.99]). High correlation (r2  = 0.99) between 1.5 T and 3.0 T QSM-BLS, with narrow reproducibility coefficients (range, [0.13, 0.21] ppm) were observed for each protocol. CONCLUSION: This work evaluated the feasibility and performance of liver QSM-BLS across iron levels and acquisition protocols at 1.5 T and 3.0 T. High correlation and reproducibility were observed between QSM-BLS and SQUID-BLS across protocols and field strengths. In summary, QSM-BLS may enable reliable and reproducible quantification of liver iron concentration.

Data adaptive regularization with reference tissue constraints for liver quantitative susceptibility mapping.

PURPOSE: To improve repeatability and reproducibility across acquisition parameters and reduce bias in quantitative susceptibility mapping (QSM) of the liver, through development of an optimized regularized reconstruction algorithm for abdominal QSM. METHODS: An optimized approach to estimation of magnetic susceptibility distribution is formulated as a constrained reconstruction problem that incorporates estimates of the input data reliability and anatomical priors available from chemical shift-encoded imaging. The proposed data-adaptive method was evaluated with respect to bias, repeatability, and reproducibility in a patient population with a wide range of liver iron concentration (LIC). The proposed method was compared to the previously proposed and validated approach in liver QSM for two multi-echo spoiled gradient-recalled echo protocols with different acquisition parameters at 3T. Linear regression was used for evaluation of QSM methods against a reference FDA-approved R 2 $$ {R}_2 $$ -based LIC measure and R 2 ∗ $$ {R}_2^{\ast } $$ measurements; repeatability/reproducibility were assessed by Bland-Altman analysis. RESULTS: The data-adaptive method produced susceptibility maps with higher subjective quality due to reduced shading artifacts. For both acquisition protocols, higher linear correlation with both R 2 $$ {R}_2 $$ - and R 2 ∗ $$ {R}_2^{\ast } $$ -based measurements were observed for the data-adaptive method ( r 2 = 0 . 74 / 0 . 69 $$ {r}^2=0.74/0.69 $$ for R 2 $$ {R}_2 $$ , 0 . 97 / 0 . 95 $$ 0.97/0.95 $$ for R 2 ∗ $$ {R}_2^{\ast } $$ ) than the standard method ( r 2 = 0 . 60 / 0 . 66 $$ {r}^2=0.60/0.66 $$ and 0 . 79 / 0 . 88 $$ 0.79/0.88 $$ ). For both protocols, the data-adaptive method enabled better test-retest repeatability (repeatability coefficients 0.19/0.30 ppm for the data-adaptive method, 0.38/0.47 ppm for the standard method) and reproducibility across protocols (reproducibility coefficient 0.28 vs. 0.53ppm) than the standard method. CONCLUSIONS: The proposed data-adaptive QSM algorithm may enable quantification of LIC with improved repeatability/reproducibility across different acquisition parameters as 3T.

A pH-/Enzyme-Responsive Nanoparticle Selectively Targets Endosomal Toll-like Receptors to Potentiate Robust Cancer Vaccination.

Toll-like receptor (TLR) agonists are potent immune-stimulators that hold great potential in vaccine adjuvants as well as cancer immunotherapy. However, TLR agonists in free form are prone to be eliminated quickly by the circulatory system and cause systemic inflammation side effects. It remains a challenge to achieve precise release of TLR7/8 agonist in the native form at the receptor site in the endosomal compartments while keeping stable encapsulation and inactive in nontarget environment. Here, we report a pH-/enzyme-responsive TLR7/8 agonist-conjugated nanovaccine (TNV), which responds intelligently to the acidic environment and cathepsin B in the endosome, precisely releases TLR7/8 agonist to activate its receptor signaling at the endosomal membrane, stimulates DCs maturation, and provokes specific cellular immunity. In vivo experiments demonstrate outstanding prophylactic and therapeutic efficacy of TNV in mouse melanoma and colon cancer. The endosome-targeted responsive nanoparticle strategy provides a potential delivery toolbox of adjuvants to advance the development of tumor nanovaccines.

Spectroscopy-based multi-parametric quantification in subjects with liver iron overload at 1.5T and 3T.

PURPOSE: To evaluate the precision profile (repeatability and reproducibility) of quantitative STEAM-MRS and to determine the relationships between multiple MR biomarkers of chronic liver disease in subjects with iron overload at both 1.5 Tesla (T) and 3T. METHODS: MRS data were acquired in patients with known or suspected liver iron overload. Two STEAM-MRS sequences (multi-TE and multi-TE-TR) were acquired at both 1.5T and 3T (same day), including test-retest acquisition. Each acquisition enabled estimation of R1, R2, and FWHM (each separately for water and fat); and proton density fat fraction. The test-retest repeatability and reproducibility across acquisition modes (multi-TE vs. multi-TE-TR) of the estimates were evaluated using intraclass correlation coefficients, linear regression, and Bland-Altman analyses. Multi-parametric relationships between parameters at each field strength, across field strengths, and with liver iron concentration were also evaluated using linear and nonlinear regression. RESULTS: Fifty-six (n = 56) subjects (10 to 73 years, 37 males/19 females) were successfully recruited. Both STEAM-MRS sequences demonstrated good-to-excellent precision (intraclass correlation coefficient ≥ 0.81) for the quantification of R1water , R2water , FWHMwater , and proton density fat fraction at both 1.5T and 3T. Additionally, several moderate (R2 = 0.50 to 0.69) to high (R2 ≥ 0.70) correlations were observed between biomarkers, across field strengths, and with liver iron concentration. CONCLUSIONS: Over a broad range of liver iron concentration, STEAM-MRS enables rapid and precise measurement of multiple biomarkers of chronic liver disease. By evaluating the multi-parametric relationships between biomarkers, this work may advance the comprehensive MRS-based assessment of chronic liver disease and may help establish biomarkers of chronic liver disease.

A feature-based convolutional neural network for reconstruction of interventional MRI.

Real-time interventional MRI (I-MRI) could help to visualize the position of the interventional feature, thus improving patient outcomes in MR-guided neurosurgery. In particular, in deep brain stimulation, real-time visualization of the intervention procedure using I-MRI could improve the accuracy of the electrode placement. However, the requirements of a high undersampling rate and fast reconstruction speed for real-time imaging pose a great challenge for reconstruction of the interventional images. Based on recent advances in deep learning (DL), we proposed a feature-based convolutional neural network (FbCNN) for reconstructing interventional images from golden-angle radially sampled data. The method was composed of two stages: (a) reconstruction of the interventional feature and (b) feature refinement and postprocessing. With only five radially sampled spokes, the interventional feature was reconstructed with a cascade CNN. The final interventional image was constructed with a refined feature and a fully sampled reference image. With a comparison of traditional reconstruction techniques and recent DL-based methods, it was shown that only FbCNN could reconstruct the interventional feature and the final interventional image. With a reconstruction time of ~ 500 ms per frame and an acceleration factor of ~ 80, it was demonstrated that FbCNN had the potential for application in real-time I-MRI.

CdSe-Decorated Flowerlike CaMoO4 Microspheres with Enhanced Hydrogen Production Activity.

Photocatalytic hydrogen production technology from water is a more effective and promising method to solve energy and environmental crises. In this work, flowerlike CaMoO4 microspheres were successfully synthesized by an ultrasonic precipitation method and modified with variable concentrations of CdSe NCs. CdSe/CaMoO4 microspheres showed increased light absorption ability, larger relative surface area, lower electrochemical impedance, and longer fluorescence lifetime. The photocatalytic hydrogen production rate of CdSe/CaMoO4 microspheres could reach up to 10 162.33 µmol g-1 h-1. The constructed type-I heterostructure improved the separation of photogenerated electrons and inhibited the rapid recombination of photogenerated electrons and holes, thus enhancing the photocatalytic hydrogen production performance. CdSe/CaMoO4 with high hydrogen production activity would be an efficient photocatalyst for hydrogen production applications.

Improved free-breathing liver fat and iron quantification using a 2D chemical shift-encoded MRI with flip angle modulation and motion-corrected averaging.

OBJECTIVES: 3D chemical shift-encoded (CSE) MRI enables accurate and precise quantification of proton density fat fraction (PDFF) and R2*, biomarkers of hepatic fat and iron deposition. Unfortunately, 3D CSE-MRI requires reliable breath-holding. Free-breathing 2D CSE-MRI with sequential radiofrequency excitation is a motion-robust alternative but suffers from low signal-to-noise-ratio (SNR). To overcome this limitation, this work explores the combination of flip angle-modulated (FAM) 2D CSE imaging with a non-local means (NLM) motion-corrected averaging technique. METHODS: In this prospective study, 35 healthy subjects (27 children/8 adults) were imaged on a 3T MRI-system. Multi-echo 3D CSE ("3D") and 2D CSE FAM ("FAM") images were acquired during breath-hold and free-breathing, respectively, to obtain PDFF and R2* maps of the liver. Multi-repetition FAM was postprocessed with direct averaging (DA)- and NLM-based averaging and compared to 3D CSE using Bland-Altmann and regression analysis. Image qualities of PDFF and R2* maps were reviewed by two radiologists using a Likert-like scale (score 1-5, 5 = best). RESULTS: Compared to 3D CSE, multi-repetition FAM-NLM showed excellent agreement (regression slope = 1.0, R2 = 0.996) for PDFF and good agreement (regression slope 1.08-1.15, R2 ≥ 0.899) for R2*. Further, multi-repetition FAM-NLM PDFF and R2* maps had fewer artifacts (score 3.8 vs. 3.2, p < 0.0001 for PDFF; score 3.2 vs. 2.6, p < 0.001 for R2*) and better overall image quality (score 4.0 vs. 3.5, p < 0.0001 for PDFF; score 3.4 vs. 2.7, p < 0.0001 for R2*). CONCLUSIONS: Free-breathing FAM-NLM provides superior image quality of the liver compared to the conventional breath-hold 3D CSE-MRI, while minimizing bias for PDFF and R2* quantification. KEY POINTS: • 2D CSE FAM-NLM is a free-breathing method for liver fat and iron quantification and viable alternative for patients unable to hold their breath. • 2D CSE FAM-NLM is a feasible alternative to breath-hold 3D CSE methods, with low bias in proton density fat fraction (PDFF) and no clinically significant bias in R2*. • Quantitatively, multiple repetitions in 2D CSE FAM-NLM lead to improved SNR.

Acute ammonia stress-induced oxidative and heat shock responses modulated by transcription factors in Litopenaeus vannamei.

The present study aimed to examine the effects of short-term exposure to ammonia on stress and oxidative responses in shrimp (Litopenaeus vannamei) and to determine whether the antioxidant system related to the regulatory role of transcription factors and stress proteins was activated. Shrimp were exposed ammonia-N at four concentrations: 0 (control), 5, 10, and 15 mg/L, for 48 h. The hepatopancreas was sampled to measure the levels of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO); the activities of superoxide dismutase (SOD), catalase (CAT), nitric oxide synthase (NOS); and the expression levels of GSH-px (encoding glutathione peroxidase), GST (encoding glutathione-S-transferase), HSP70 (encoding heat shock protein 70), HSP90 (encoding heat shock protein 90), p53, RELISH, and AKIRIN. We observed that exposure to a high ammonia content increased the abundance of oxidative factors (MDA, CAT, SOD, NOS, and NO), reduced the levels of GSH, and upregulated the mRNA expression levels of antioxidant genes (GSH-px and GST), stress-related genes (HSP70 and HSP90), and transcription factor genes (p53, RELISH, and AKIRIN). These results indicated that ammonia induced oxidative stress and inflammation. Both enzymatic and nonenzymatic antioxidant defense systems are involved, which might be regulated by HSPs, as well as certain transcription factors, such as p53 and nuclear factor kappa B (NF-κB), thus mounting an adaptive response to help rebalance redox homoeostasis.

A pH-Responsive Nanoparticle Library with Precise pH Tunability by Co-Polymerization with Non-Ionizable Monomers.

Precise monitoring of the subtle pH fluctuation during biological events remains a big challenge. Previously, we reported an ultra-pH-sensitive (UPS) nanoprobe library with a sharp pH response using co-polymerization of two tertiary amine-containing monomers with distinct pKa . Currently, we have generalized the UPS nanoparticle library with tunable pH transitions (pHt ) by copolymerization of a tertiary amine-containing monomer with a series of non-ionizable monomers. The pHt of nanoparticles is fine-tuned by the non-ionizable monomers with different hydrophobicity. Each non-ionizable monomer presents a constant contribution to pH tunability regardless of tertiary amine-containing monomers. Based on this strategy, we produced two libraries of nanoprobes with continuous pHt covering the entire physiological pH range (5.0-7.4) for fluorescent imaging of endosome maturation and cancers. This generalized strategy provides a powerful toolkit for biological studies and cancer theranostics.

Knockdown of circBFAR inhibits proliferation and glycolysis in gastric cancer by sponging miR-513a-3p/hexokinase 2 axis.

The relationship between circular RNAs (circRNAs) and many types of cancer has been of great interest. A novel circRNA, circBFAR, has been identified, but the functions of circBFAR and its underlying mechanism in gastric cancer (GC) have not been reported. This study was designed to investigate the role of circBFAR in GC and its downstream miRNA targets. Quantitative real-time polymerase reaction was used to detect the expression of circBFAR and miRNAs. Cell counting kit-8 and EdU were used to detect the proliferation of GC cells. Measurement of the extracellular acidification rate, oxygen consumption rate and lactate acid production were performed to assess the glycolysis levels. The results showed that circBFAR exhibited higher expression in GC tissues and cell lines. circBFAR was proven to promote GC proliferation by targeting the miR-513a-3p/hexokinase 2 (HK2) axis. Inhibition of circBFAR also led to a significant decrease in the glycolysis levels. In this study, we found a circBFAR/miR-513a-3p/HK2 axis in GC and revealed the relationship between circBFAR and glycolysis for the first time. circBFAR may serve as a novel target of GC individualized therapy.

Design and evaluation of quantitative MRI phantoms to mimic the simultaneous presence of fat, iron, and fibrosis in the liver.

PURPOSE: To design, construct, and evaluate quantitative MR phantoms that mimic MRI signals from the liver with simultaneous control of three parameters: proton-density fat fraction (PDFF), R2∗ , and T1 . These parameters are established biomarkers of hepatic steatosis, iron overload, and fibrosis/inflammation, respectively, which can occur simultaneously in the liver. METHODS: Phantoms including multiple vials were constructed. Peanut oil was used to modulate PDFF, MnCl2 and iron microspheres were used to modulate R2∗ , and NiCl2 was used to modulate the T1 of water (T1,water ). Phantoms were evaluated at both 1.5 T and 3 T using stimulated-echo acquisition-mode MRS and chemical shift-encoded MRI. Stimulated-echo acquisition-mode MRS data were processed to estimate T1,water , T1,fat , R2,water∗ , and R2,fat∗ for each vial. Chemical shift-encoded MRI data were processed to generate PDFF and R2∗ maps, and measurements were obtained in each vial. Measurements were evaluated using linear regression and Bland-Altman analysis. RESULTS: High-quality PDFF and R2∗ maps were obtained with homogeneous values throughout each vial. High correlation was observed between imaging PDFF with target PDFF (slope = 0.94-0.97, R2 = 0.994-0.997) and imaging R2∗ with target R2∗ (slope = 0.84-0.88, R2 = 0.935-0.943) at both 1.5 T and 3 T. The values of R2,fat∗ and R2,water∗ were highly correlated with slope close to 1.0 at both 1.5 T (slope = 0.90, R2 = 0.988) and 3 T (slope = 0.99, R2 = 0.959), similar to the behavior observed in vivo. The value of T1,water (500-1200 ms) was controlled with varying NiCl2 concentration, while T1,fat (300 ms) was independent of NiCl2 concentration. CONCLUSION: Novel quantitative MRI phantoms that mimic the simultaneous presence of fat, iron, and fibrosis in the liver were successfully developed and validated.

Temperature-corrected proton density fat fraction estimation using chemical shift-encoded MRI in phantoms.

PURPOSE: Chemical shift-encoded MRI (CSE-MRI) is well-established to quantify proton density fat fraction (PDFF) as a quantitative biomarker of hepatic steatosis. However, temperature is known to bias PDFF estimation in phantom studies. In this study, strategies were developed and evaluated to correct for the effects of temperature on PDFF estimation through simulations, temperature-controlled experiments, and a multi-center, multi-vendor phantom study. THEORY AND METHODS: A technical solution that assumes and automatically estimates a uniform, global temperature throughout the phantom is proposed. Computer simulations modeled the effect of temperature on PDFF estimation using magnitude-, complex-, and hybrid-based CSE-MRI methods. Phantom experiments were performed to assess the temperature correction on PDFF estimation at controlled phantom temperatures. To assess the temperature correction method on a larger scale, the proposed method was applied to data acquired as part of a nine-site multi-vendor phantom study and compared to temperature-corrected PDFF estimation using an a priori guess for ambient room temperature. RESULTS: Simulations and temperature-controlled experiments show that as temperature deviates further from the assumed temperature, PDFF bias increases. Using the proposed correction method and a reasonable a priori guess for ambient temperature, PDFF bias and variability were reduced using magnitude-based CSE-MRI, across MRI systems, field strengths, protocols, and varying phantom temperature. Complex and hybrid methods showed little PDFF bias and variability both before and after correction. CONCLUSION: Correction for temperature reduces temperature-related PDFF bias and variability in phantoms across MRI vendors, sites, field strengths, and protocols for magnitude-based CSE-MRI, even without a priori information about the temperature.

Glucose starvation suppresses gastric cancer through targeting miR-216a-5p/Farnesyl-Diphosphate Farnesyltransferase 1 axis.

BACKGROUND: Fasting mimic diet is an effect approach for gastric cancer (GC) treatment. Exploring mechanisms of glucose deprivation-mediated GC suppression is required to develop novel therapeutic regimens. Farnesyltransferase 1 (FDFT1), as a novel target in basic research, has been reported to regulate malignant progression in some types of cancer. However, biological functions of FDFT1 in GC are still unclear. This study focused on biological functions of FDFT1 in GC and the association between glucose starvation (GS) and FDFT1. METHODS: The data derived from the Kaplan-Meier Plotter database were collected to identify the relationship between survival time and FDFT1 expression levels of GC patients. Bioinformatic analysis was performed to explore the biological functions of FDFT1. The expression levels of targeted genes and microRNAs (miRNAs) were detected with immunohistochemistry, quantitative real-time PCR and western blot. Malignant behaviors were measured using cell counting, cell counting kit-8, 5-ethynyl-2-deoxyuridine, wound healing, invasion transwell assays in vitro and constructions of subcutaneous and lung-metastatic tumors in vivo. The glycolysis of GC cells was determined by a series of metabolites, including lactate acid, pyruvic acid, ATP production, rates of glucose uptake, extracellular acidification rate and oxygen consumption rate. RESULTS: FDFT1 was downregulated in GC and negatively correlated with pathological T stage, pathological TNM stage and cancer differentiation. High expression of FDFT1 also indicated better prognosis of GC patients. FDFT1 upregulation attenuated proliferation, migration and invasion of GC. miR-216a-5p was identified as a critical suppressor of FDFT1 expression and miR-216a-5p/FDFT1 axis regulated malignant behaviors and glycolysis of GC cells. GS suppressed malignant behaviors of GC by targeting miR-216a-5p/FDFT1 axis both in vitro and in vivo. CONCLUSION: This study illustrated novel mechanisms by which GS effectively suppresses GC. FDFT1 may become a potential prognostic indicator and novel target of GC therapy.

Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation.

BACKGROUND: Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. METHODS: Correlation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan-Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism. RESULTS: Correlation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo. CONCLUSIONS: Downregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

Limits of Fat Quantification in the Presence of Iron Overload.

BACKGROUND: Chemical shift encoded magnetic resonance imaging (CSE-MRI)-based tissue fat quantification is confounded by increased R2* signal decay rate caused by the presence of excess iron deposition. PURPOSE: To determine the upper limit of R2* above which it is no longer feasible to quantify proton density fat fraction (PDFF) reliably, using CSE-MRI. STUDY TYPE: Prospective. POPULATION: Cramér-Rao lower bound (CRLB) calculations, Monte Carlo simulations, phantom experiments, and a prospective study in 26 patients with known or suspected liver iron overload. FIELD STRENGTH/SEQUENCE: Multiecho gradient echo at 1.5 T and 3.0 T. ASSESSMENT: CRLB calculations were used to develop an empirical relationship between the maximum R2* value above which PDFF estimation will achieve a desired number of effective signal averages. A single voxel multi-TR, multi-TE stimulated echo acquisition mode magnetic resonance spectroscopy acquisition was used as a reference standard to estimate PDFF. Reconstructed PDFF and R2* maps were analyzed by one analyst using multiple regions of interest drawn in all nine Couinaud segments. STATISTICAL TESTS: None. RESULTS: Simulations, phantom experiments, and in vivo measurements demonstrated unreliable PDFF estimates with increased R2*, with PDFF errors as large as 20% at an R2* of 1000 s-1 . For typical optimized Cartesian acquisitions (TE1 = 0.75 msec, ΔTE = 0.67 msec at 1.5 T, TE1 = 0.65 msec, ΔTE = 0.58 msec at 3.0 T), an empirical relationship between PDFF estimation errors and acquisition parameters was developed that suggests PDFF estimates are unreliable above an R2* of ~538 s-1 and ~779 s-1 at 1.5 T and 3 T, respectively. This empirical relationship was further investigated with phantom experiments and in vivo measurements, with PDFF errors at an R2* of 1000 s-1 at 3.0 T as large as 10% with TE1 = 1.24 msec, ΔTE = 1.01 msec compared to 3% with TE1 = 0.65 msec, ΔTE = 0.58 msec. DATA CONCLUSION: We successfully developed a theoretically-based empirical formula that may provide an easily calculable guideline to identify R2* values above which PDFF is not reliable in research and clinical applications using CSE-MRI to quantify PDFF in the presence of iron overload. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

pH-Amplified CRET Nanoparticles for In Vivo Imaging of Tumor Metastatic Lymph Nodes.

Noninvasive imaging strategies have been extensively investigated for in vivo mapping of sentinel lymph nodes (SLNs). However, the current imaging strategies fail to accurately assess tumor metastatic status in SLNs with high sensitivity. Here we report pH-amplified self-illuminating near-infrared nanoparticles, which integrate chemiluminescence resonance energy transfer (CRET) and signal amplification strategy, enabling accurate identification of metastatic SLNs. After draining into lymph nodes, the nanoparticles were phagocytosed and dissociated in acidic phagosomes of inflammatory macrophages to emit near-infrared luminescent light. Using these nanoparticles, we successfully differentiated tumor metastatic lymph nodes from benign ones. These nanoparticles also exhibited excellent imaging capability for early detection of metastatic SLNs in diverse animal tumor models with small tumor volume (100-200 mm3 ).

Motion-robust, high-SNR liver fat quantification using a 2D sequential acquisition with a variable flip angle approach.

PURPOSE: Chemical shift encoded (CSE)-MRI enables quantification of proton-density fat fraction (PDFF) as a biomarker of liver fat content. However, conventional 3D Cartesian CSE-MRI methods require breath-holding. A motion-robust 2D Cartesian sequential method addresses this limitation but suffers from low SNR. In this work, a novel free breathing 2D Cartesian sequential CSE-MRI method using a variable flip angle approach with centric phase encoding (VFA-centric) is developed to achieve fat quantification with low T1 bias, high SNR, and minimal blurring. METHODS: Numerical simulation was performed for variable flip angle schedule design and preliminary evaluation of VFA-centric method, along with several alternative flip angle designs. Phantom, adults (n = 8), and children (n = 27) were imaged at 3T. Multi-echo images were acquired and PDFF maps were estimated. PDFF standard deviation was used as a surrogate for SNR. RESULTS: In both simulation and phantom experiments, the VFA-centric method enabled higher SNR imaging with minimal T1 bias and blurring artifacts. High correlation (slope = 1.00, intercept = 0.04, R2 = 0.998) was observed in vivo between the proposed VFA-centric method obtained PDFF and reference PDFF (free breathing low-flip angle 2D sequential acquisition). Further, the proposed VFA-centric method (PDFF standard deviation = 1.5%) had a better SNR performance than the reference acquisition (PDFF standard deviation = 3.3%) with P < .001. CONCLUSIONS: The proposed free breathing 2D Cartesian sequential CSE-MRI method with variable flip angle approach and centric-ordered phase encoding achieved motion robustness, low T1 bias, high SNR compared to previous 2D sequential methods, and low blurring in liver fat quantification.