The Value of Amide Proton Transfer MRI in the Diagnosis of Malignant and Benign Urinary Bladder Lesions: Comparison With Diffusion-Weighted Imaging.

BACKGROUND: Conventional magnetic resonance imaging (MRI) has certain limitations in distinguishing between malignant and benign urinary bladder (UB) lesions. Amide proton transfer (APT) imaging may provide more diagnostic information than diffusion-weighted imaging (DWI) to distinguish between malignant and benign UB. PURPOSE: To investigate the potential of APT imaging in the diagnosis of malignant and benign UB lesions and to compare its diagnostic efficacy with that of conventional DWI. STUDY TYPE: Prospective. SUBJECTS: Eighty patients with UB lesions. FIELD STRENGTH/SEQUENCE: A 3.0 T/turbo spin echo (TSE) T1-weighted and T2-weighted imaging, single-shot echo planar DWI, and three-dimensional TSE APT imaging. ASSESSMENT: Patients underwent radical cystectomy or transurethral resection of the bladder lesions within 2 weeks after CT urography and MRI examination. APT signal intensity in UB lesions was quantified by the asymmetric magnetization transfer ratio (MTRasym ). MTRasym and apparent diffusion coefficient (ADC) values were measured and compared between malignant and benign UB lesions. STATISTICAL TESTS: Kolmogorov-Smirnov test, Student's t test or Mann-Whitney U test, Spearman rank correlation coefficient, area under the receiver operating characteristic (ROC) curve (AUC), Delong test, and intraclass correlation coefficient (ICC). The significance threshold was set at P < 0.05. RESULTS: Thirty-two patients had pathologically confirmed benign UB lesions, including 2 bladder leiomyomas, 1 submucosal amyloidosis, 1 inflammatory myofibroblastic tumor, and 28 inflammatory lesions, and 48 patients had pathologically confirmed urothelial carcinoma. Urothelial carcinomas showed significantly higher MTRasym values (1.53% [0.74%] vs. 0.85% [0.23%]) and significantly lower ADC values (1.24 ± 0.34 × 10-3 mm2 /s vs. 1.43 ± 0.22 × 10-3 mm2 /s) than benign UB lesions. The MTRasym value (AUC = 0.928) was significantly better in differentiating urothelial carcinoma from benign UB lesions than the ADC value (AUC = 0.722). DATA CONCLUSION: APT imaging may have value in discriminating malignant from benign UB lesions and has better diagnostic performance than DWI. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Amide proton transfer-weighted magnetic resonance imaging for application in renal fibrosis: A radiological-pathological based analysis.

BACKGROUND: Renal fibrosis (RF) being the most important pathological change in the progression of CKD, is currently assessed by the evaluation of a biopsy. This present study aimed to apply a novel functional MRI (fMRI) protocol named amide proton transfer weighting (APTw) to evaluate RF non-invasively. METHODS: Male Sprague-Dawley (SD) rats were initially subjected to bilateral kidney ischemia/reperfusion injury (IRI), unilateral ureteral obstruction (UUO) and Sham operation, respectively. All rats underwent APT mapping on the 7th and the 14th day after operation. Besides, 26 patients undergoing renal biopsy at the Nephrology Department of Shanghai Tongji Hospital between July 2022 and May 2023. Patients underwent APT and apparent diffusion coefficient (ADC) mappings within 1 week before biopsy. MRI results of both patients and rats were calculated by comparing with gold standard histology for fibrosis assessment. RESULTS: In animal models, the cortical APT (cAPT) and medullary APT (mAPT) values were positively correlated with the degree of renal fibrosis. Compared to the sham group, IRI group showed significantly increased cAPT and mAPT values on the 7th and 14th day after surgery, but no group differences were found in ADC values. Similar results were found in human patients. Cortical/medullary APT values were significantly increased in patients with moderate-to-severe fibrosis than patients with mild fibrosis. ROC curve analysis indicated that APT value displayed a better diagnostic value for RF. Furthermore, combination of cADC and cAPT improved fibrosis detection by imaging variables alone (p<0.1). CONCLUSION: APT values had better diagnostic capability at early stage of RF compared to ADC values, and the addition of APT imaging to conventional ADC will significantly improve the diagnostic performance for predicting kidney fibrosis.

Evaluation of amide proton transfer imaging for bladder cancer histopathologic features: A comparative study with diffusion- weighted imaging.

PURPOSE: To assess the ability of amide proton transfer (APT) imaging, in comparison with diffusion-weighted imaging (DWI), to differentiate low-grade from high-grade bladder tumors and predict the aggressiveness of bladder cancer (BCa). METHODS: Forty-eight patients diagnosed with BCa confirmed by histopathological findings who underwent magnetic resonance (MR) imaging, including APT imaging and DWI (b = 0, 1000 sec/mm2), were enrolled in this study. The asymmetric magnetization transfer ratio (MTRasym) was defined as the magnetization transfer asymmetry at 3.5 ppm. MTRasym and apparent diffusion coefficients (ADCs) were compared between the low- and high-grade groups and between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) in terms of the areas under the receiver operating characteristic curves (AUCs). RESULTS: The MTRasym values were significantly higher in patients with high-grade bladder tumors than in those with low-grade tumors (1.61 % [0.76 %], 1.12 ± 0.3 %; P = 0.000) and in MIBC than in NMIBC (2.53 ± 0.67 %, 1.38 % [0.35 %]; P = 0.000). The AUCs of MTRasym were significantly larger than those of ADC for differentiating MIBC from NMIBC (0.973, 0.771; P = 0.016). Adding APT imaging to DWI significantly improved the diagnostic accuracy for differentiating MIBC from NMIBC versus DWI alone (0.985, 0.876; P = 0.013). CONCLUSIONS: APT imaging can predict tumor grade and aggressiveness in BCa. The diagnostic performance of APT imaging in predicting tumor aggressiveness was better than that of DWI, and adding APT imaging to DWI significantly improved the diagnostic accuracy of predicting tumor aggressiveness versus DWI alone.

Author Correction: Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Combination of Sonographic Morphology Score and Tumor Markers for Detecting Postoperative Recurrent Pelvic Ovarian Carcinoma: Compared With MRI Assessment.

To assess the efficacy of the combination of sonographic morphology score (SMS) with CA125 and HE4 for detecting recurrent pelvic ovarian carcinoma (OC). Data of 58 OC patients treated in our hospital between 2014 and 2016 were analyzed. After cytoreductive surgery and routine chemotherapy, all patients were followed up by transvaginal ultrasound examination (SMS for pelvic masses based on volume and structure scores) and tumor marker (serum CA125 and HE4) detection. Clinical diagnosis of recurrent OC was based on physical examination, magnetic resonance imaging, and punctured pathology for pelvic masses. Receiver operating characteristic (ROC) curves of SMS and the tumor markers were generated, and areas under the curve (AUC) values were assessed. There were 26 patients with tumor recurrence and 32 cases with no recurrence. Magnetic resonance imaging had 100% sensitivity and specificity. The areas under the ROC curves of SMS, CA125, HE4, and SMS-CA125-HE4 were 0.816, 0.825, 0.737, and 0.903, respectively. There was no significant difference in AUC values between SMS and CA125 or HE4. There were significant differences in AUC values between SMS-CA125-HE4 and SMS (Z = 2.48, P = 0.042), CA125 (Z = 2.38, P = 0.046), and HE4 (Z = 6.48, P = 0.016), respectively. With a cutoff value of SMS, 5; CA125, 35 U/mL; HE4, 105 pmol/L, the sensitivity, specificity, positive prognostic value, and negative prognostic value of SMS-CA125-HE4 for recurrent OC assessment were 0.9231, 0.8438, 0.8276, and 0.931, respectively. SMS-CA125-HE4 was correlated with recurrent OC (χ = 30.7428, P < 0.0001). Ultrasound combined with tumor markers may improve the diagnostic efficiency of recurrent OC.

Marine-derived chromopeptide A, a novel class I HDAC inhibitor, suppresses human prostate cancer cell proliferation and migration.

Histone deacetylases (HDACs), especially HDAC1, 2, 3 and 4, are abundantly expressed and over-activated in prostate cancer that is correlated with the poor prognosis. Thus, inhibition of HDAC activity has emerged as a potential alternative option for prostate cancer therapy. Chromopeptide A is a depsipeptide isolated from the marine sediment-derived bacterium Chromobacterium sp. HS-13-94; it has a chemical structure highly similar to FK228, a class I HDAC inhibitor that is approved by FDA for treating T-cell lymphoma. In this study, we determined whether chromopeptide A, like FK228, acted as a class I HDAC inhibitor, and whether chromopeptide A could inhibit the growth and migration of human prostate cancer in vitro and in vivo. HDAC enzyme selectivity and kinetic analysis revealed that chromopeptide A selectively inhibited the enzymatic activities of HDAC1, 2, 3 and 8 in a substrate non-competitive manner with comparable IC50 values for each HDAC member as FK228 in vitro. Importantly, chromopeptide A dose-dependently suppressed the proliferation of human prostate cancer cell lines PC3, DU145 and LNCaP with IC50 values of 2.43±0.02, 2.08±0.16, and 1.75±0.06 nmol/L, respectively, accompanied by dose-dependent inhibition of HDAC enzymatic activity in PC3 and DU145 cells. Chromopeptide A (0.2-50 nmol/L) caused G2/M phase arrest and induced apoptosis in the prostate cancer cell lines. Moreover, chromopeptide A dose-dependently inhibited the migration of PC3 cells. In mice bearing PC3 prostate cancer xenografts, intravenous injection of chromopeptide A (1.6, 3.2 mg/kg, once a week for 18 d) significantly suppressed the tumor growth, which was associated with increased expression levels of Ac-H3 and p21 in tumor tissues. Our results identify chromopeptide A as a novel class I HDAC inhibitor and provide therapeutic strategies that may be implemented in prostate cancer.

Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells.

AIM: Inhibition of heat shock protein (Hsp90) has been proven to be effective in overriding primary and acquired resistance of kinase inhibitors. In this study, we investigated the role of FS-108, a newly developed Hsp90 inhibitor, to overcome gefitinib resistance in EGFR mutant non-small cell lung cancer cells. METHODS: Cell proliferation was assessed using the SRB assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression was examined by Western blotting. The in vivo effectiveness of FS-108 was determined in an NCI-H1975 subcutaneous xenograft model. RESULTS: FS-108 triggered obvious growth inhibition in gefitinib-resistant HCC827/GR6, NCI-H1650 and NCI-H1975 cells through inducing G2/M phase arrest and apoptosis. FS-108 treatment resulted in a remarkable degradation of key client proteins involved in gefitinib resistance and further abrogated their downstream signaling pathways. Interestingly, FS-108 alone exerted an identical or superior effect on circumventing gefitinib resistance compared to combined kinase inhibition. Finally, the ability of FS-108 to overcome gefitinib resistance in vivo was validated in an NCI-H1975 xenograft model. CONCLUSION: FS-108 is a powerful agent that impacts the survival of gefitinib-resistant cells in vitro and in vivo through targeting Hsp90.

[Polyelectrolyte layer-by-layer assembled lipid nanoparticles for improving oral absorption of doxorubicin].

Polyelectrolyte layer-by-layer assembled lipid nanoparticles (NPs) were prepared to improve their stability against lipolysis in gastrointestinal tract, and efficiency of oral absorption of doxorubicin (DOX). The lipid NPs were prepared by hot melt-probe sonication method. The polyelectrolyte layer-by-layer assembled lipid NPs (DOX-NPs/CS/γ-PGA) was prepared by layer-by-layer self-assembling polyelectrolytes cationic chitosan (CS) and anionic poly (γ-glutamic acid) (γ-PGA) on the surface of lipid NPs based on electrostatic interaction. The particle size, polydispersity index (PDI) and zeta potential of lipid NPs and DOX-NPs/CS/γ-PGA were determined by dynamic light scattering (DLS). The in vitro drug release was determined in p H 1.2 HCl solution and p H 6.8 phosphate buffer solution (PBS). The stability of lipid NPs against lipolysis was evaluated in simulated gastrointestinal medium containing lipase. The cellular uptake of lipid NPs and DOX-NPs/CS/γ-PGA was evaluated in Caco-2 cell model. The pharmacokinetic of DOX after oral absorption was studied in SD rats. Results showed that the average particle size and zeta potential of DOX-NPs/CS/γ-PGA were 180.6 ± 5.4 nm and-38.53 ± 0.29 m V, respectively. The DOX-NPs/CS/γ-PGA effectively slowed down the release of DOX from nanoparticles, and decreased the lipolysis of lipid NPs in simulated gastrointestinal medium. The cell study showed that DOX-loaded lipid NPs and DOX-NPs/CS/ γ-PGA remarkably enhanced the cell uptake in comparison with DOX solution. The DOX-NPs/CS/γ-PGA significantly improved oral absorption of DOX compared with DOX-loaded lipid NPs. The C(max), t(max) were 0.76 ± 0.25 µg·m L(-1) and 0.5 h, respectively; AUC(0-24 h) was 3.02 folds and the relative bioavailability was 302.46% with DOX solution as reference. The stability of lipid NPs against lipolysis and drug release were significantly improved by layer-by-layer assembling, leading to an improved oral absorption.

Multifunctional nanocomposite based on graphene oxide for in vitro hepatocarcinoma diagnosis and treatment.

Because of its unique chemical and physical properties, graphene oxide (GO) has attracted a large number of researchers to explore its biomedical applications in the past few years. Here, we synthesized a novel multifunctional nanocomposite based on GO and systemically investigated its applications for in vitro hepatocarcinoma diagnosis and treatment. This multifunctional nanocomposite named GO-PEG-FA/Gd/DOX was obtained as the following procedures: gadolinium-diethylenetriamine-pentaacetic acid-poly(diallyl dimethylammonium) chloride (Gd-DTPA-PDDA) as magnetic resonance imaging (MRI) probe was applied to modify GO by simple physical sorption with a loading efficiency of Gd(3+) up to 0.314 mg mg(-1). In order to improve its tumor targeting imaging and treatment efficiency, the obtained intermediate product was further modified with folic acid (FA). Finally, the nanocomposite was allowed to load anticancer drug doxorubicin hydrochloride via π-π stacking and hydrophobic interaction with the loading capacity reaching 1.38 mg mg(-1). MRI test revealed that GO-PEG-FA/Gd/DOX exhibit superior tumor targeting imaging efficiency over free Gd(3+). The in vitro release of DOX from the nanocomposite under tumor relevant condition (pH 5.5) was fast at the initial 10 h and then become relatively slow afterward. Moreover, we experimentally demonstrated that the multifunctional nanocomposite exhibited obviously cytotoxic effect upon cancer cells. Above results are promising for the next in vivo experiment and make it possible to be a potential candidate for malignancy early detection and specific treatment.

alpha2,6-hyposialylation of c-Met abolishes cell motility of ST6Gal-I-knockdown HCT116 cells.

AIM: We aimed to investigate the potential modification of previously unrecognized surface glycoprotein(s) by alpha2,6-sialylation other than by integrins. METHODS: The expression of beta-galactoside alpha2,6-sialyltransferase (ST6Gal-I) in the colon cancer cell line HCT116 was reduced by siRNA. The adhesion and Boyden chamber assay were used to detect the variation in cell motility. alpha2,6-Sialylation proteins were detected with lectin affinity assay. The mRNA expression, protein expression and downstream signaling modulation with siRNA were detected using reverse transcription-polymerase chain reaction, flow cytometry analysis, and Western blot. RESULTS: In HCT116 cells, the knockdown of ST6Gal-I inhibited cell motility, but did not affect cell adhesion. This selectively altered cell migration was caused by the loss of alpha2,6-sialic acid structures on c-Met. Moreover, STAT3 was dephosphorylated at tyrosine 705 in ST6Gal-I-knockdown (ST6Gal-I-KD) HCT116 cells. CONCLUSION: c-Met is the substrate of ST6Gal-I. The hyposialylation of c-Met can abolish cell motility in ST6Gal-I-KD HCT116 cells.Acta Pharmacologica Sinica (2009) 30: 1039-1045; doi: 10.1038/aps.2009.84; published online 1 June 2009.