Exchange-mediated contrast agents for spin-lock imaging

Measurements of relaxation rates in the rotating frame with spin-locking techniques are sensitive to substances with exchanging protons with appropriate chemical shifts. The authors develop a novel approach to exchange-rate selective imaging based on measured T(1ρ) dispersion with applied locking field strength, and demonstrate the method on samples containing the X-ray contrast agent Iohexol with and without cross-linked bovine serum albumin. T(1ρ) dispersion of water in the phantoms was measured with a Varian 9.4-T magnet by an on-resonance spin-locking pulse with fast spin-echo readout, and the results used to estimate exchange rates. The Iohexol phantom alone gave a fitted exchange rate of ~1 kHz, bovine serum albumin alone was ~11 kHz, and in combination gave rates in between. By using these estimated rates, we demonstrate how a novel spin-locking imaging method may be used to enhance contrast due to the presence of a contrast agent whose protons have specific exchange rates.     

Elevated plasma osteopontin level is predictive of cirrhosis in patients with hepatitis B infection

Background: Osteopontin (OPN) was shown to play an important role in the pathogenesis of various inflammatory and fibrotic processes and elevated in fibrotic liver of mouse model. However, the significance of OPN in hepatitis B virus (HBV)‐induced liver cirrhosis (LC) remains unclear and is therefore evaluated in this study. Methods: Thirty‐nine patients with HBV‐induced LC, 30 patients with HBV infection but without cirrhosis, 11 patients with HBV‐related hepatocellular carcinoma (HCC) and 14 additional healthy controls were enrolled in this study. Plasma levels of OPN were measured with enzyme‐linked immunosorbent assay and the relationship between OPN and clinical parameters was evaluated. Results: When compared to HBV infection group (median 2.16 ng/ml), plasma levels of OPN were significantly increased in cirrhosis (4.52 ng/ml, p < 0.001) and cancer group (13.38 ng/ml, p < 0.001). The OPN level was correlated with the severity of liver damage according to Child–Pugh classification (p = 0.003). It showed at least comparable sensitivity and specificity to predict cirrhosis as aspartate aminotransferase to platelet ratio index, a previously established non‐invasive serum marker of cirrhosis. Conclusions: These data suggest that OPN could be used to evaluate the existence of LC, as OPN has previously been reported to be increased in the HCC; this unique feature makes OPN a promising candidate for prediction biomarker in the long‐time surveillance of patients with HBV infection to evaluate the risk of cirrhosis and cancer.     

Involvement of the tyrosinase gene in the deposition of cardiac lipofuscin in mice. Association with aortic fatty streak development.

Lipofuscin pigment, a terminal oxidation product, accumulates within cells during the normal aging process and under certain pathological conditions. We have analyzed a genetic cross between two inbred mouse strains, BALB/cJ and a subline of C57BL/6J, which differ in lipofuscin deposition. A comparison of the segregation pattern of cardiac lipofuscin with the albino locus (c) on mouse chromosome 7 revealed complete concordance. Analysis of spontaneous mutants of the tyrosinase gene, encoded by the albino locus, confirmed that the tyrosinase gene itself controls lipofuscin formation. Genetic analysis of other strains indicated that one or more additional genes cab contribute to the inheritance of lipofuscin. We also present evidence for an association between cardiac lipofuscin deposition and aortic fatty streak development in the mouse.     

Ultrasound-based elastography: a novel approach to assess radio frequency ablation of liver masses performed with expandable ablation probes: a feasibility study

OBJECTIVE: The purpose of this study was to evaluate the technical feasibility of ultrasound-based elastography as a tool for assessing the size and shape of the coagulation necrosis caused by radio frequency ablation (RFA) probes using expandable electrodes ex vivo as well as in a patient with a liver metastasis. METHODS: A commercially available expandable RFA probe was used to create a 3-cm ablation in a piece of bovine liver. The ablation probe was used in situ to induce tissue deformation for elastography before and after ablation. Ultrasonic radio frequency data were processed to generate elasticity strain images. The appearance of the ablation zone was compared with magnetic resonance imaging and a gross section specimen. One patient with malignant metastatic disease to the liver and a clinical indication for RFA was investigated for the feasibility of percutaneous elastography of RFA using the same technique. Sonographic strain images were compared with the appearance of the nonenhancing ablation zone on contrast-enhanced computed tomography. RESULTS: Ex vivo, the ablation zone on ultrasound-based elastography was represented by an area of increased stiffness and was well demarcated from the nonablated surrounding tissue. The size and shape of the ablated zone on the strain image correlated well with the gross specimen and the magnetic resonance imaging appearance. Strain images obtained from the patient showed results similar to those of the ex vivo experiment and correlated well with the nonenhancing area of ablation on contrast-enhanced computed tomography. CONCLUSIONS: Ultrasound-based elastography may be a promising tool for displaying the ablation zone created by expandable RFA probes.     

Performance of Fasting Plasma Glucose and Postprandial Urine Glucose in Screening for Diabetes in Chinese High-risk Population

Background:

The conventional approaches to diabetes screening are potentially limited by poor compliance and laboratory demand. This study aimed to evaluate the performance of fasting plasma glucose (FPG) and postprandial urine glucose (PUG) in screening for diabetes in Chinese high-risk population.

Methods:

Nine hundred and nine subjects with high-risk factors of diabetes underwent oral glucose tolerance test after an overnight fast. FPG, hemoglobin A1c, 2-h plasma glucose (2 h-PG), and 2 h-PUG were evaluated. Diabetes and prediabetes were defined by the American Diabetes Association criteria. The area under the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic accuracy of 2 h-PUG, and the optimal cut-off determined to provide the largest Youden index. Spearman correlation was used for relationship analysis.

Results:

Among 909 subjects, 33.4% (304/909) of subjects had prediabetes, and 17.2% (156/909) had diabetes. The 2 h-PUG was positively related to FPG and 2 h-PG (r = 0.428 and 0.551, respectively, both P < 0.001). For estimation of 2 h-PG ≥ 7.8 mmol/L and 2 h-PG ≥ 11.1 mmol/L using 2 h-PUG, the area under the ROC curve were 0.772 (95% confidence interval [CI ]: 0.738–0.806) and 0.885 (95% CI: 0.850–0.921), respectively. The corresponding optimal cut-offs for 2 h-PUG were 5.6 mmol/L and 7.5 mmol/L, respectively. Compared with FPG alone, FPG combined with 2 h-PUG had a higher sensitivity for detecting glucose abnormalities (84.1% vs. 73.7%, P < 0.001) and diabetes (82.7% vs. 48.1%, P < 0.001).

Conclusion:

FPG combined with 2 h-PUG substantially improves the sensitivity in detecting prediabetes and diabetes relative to FPG alone, and may represent an efficient layperson-oriented diabetes screening method.     

Relationship between the expression of MDR1 in hepatocellular cancer and its biological behaviors

Objective: By the detection of HBV infection, AFP and AST, the targets of biological behavior and the gene expression of multi-drug resistance gene 1 (MDR1) in hepatocellular carcinoma (HCC), we investigate characteristics of the expression of MDR1 in HCC and its relationship with HCC biological behavior. Methods: Using real-time fluorescence quantitative PCR (FQ-PCR) to detect the expressions of MDR1 in 102 samples of HCC tissue and 20 samples of non-cancerous tissue, we analyze the relationship between expressions of MDR1 and biological characteristics of HCC. Results: The expression of MDR1 in HCC is 0.55±0.27, and in normal liver tissues is 0.23±0.10, respectively. The expression in HCC is higher than it in normal liver tissue, the difference is statistically significant (P<0.05) and the difference between the expression and the HCC envelopes is statistically significant, and the expression increases along with the increase of Edmondson classification (P<0.05). HBV infection, AFP positive, the rise of AST, all these factors have positive correlations with the expression (r=0.463, 0.473, 0.299). In MDR1 expressions of HCC patients, the survival curve of the negative is higher than that of the positive, but the difference is not statistically significant. Conclusion: There are drug resistance phenomena in HCC, MDR1 expression may play an important role in primary HCC drug resistance. HBV infection can be detected as a reference indicator of HCC chemotherapy resistance, plasma levels of AFP, AST can be used as a reference index change dynamic monitoring of MDR1 expression.     

FRZB up-regulation is correlated with hepatic metastasis and poor prognosis in colon carcinoma patients with hepatic metastasis

Frizzled-related protein (FRZB) was up-regulated in hepatic metastasis samples compared with primary colon cancer samples in our previous work. However, the clinical relevance of FRZB in colon cancer hepatic metastasis remains uncertain. The aim of this study was to assess the prognostic value of FRZB in patients with colon carcinoma hepatic metastasis after hepatic resection. FRZB expression was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) primary colon carcinoma and paired hepatic metastasis tissues from 136 patients with liver metastasis from colon carcinoma that underwent hepatic resection. The relation between FRZB expression and clinicopathologic factors and long-term prognosis in these 136 patients was retrospectively examined. The prognostic significance of negative or positive FRZB exspression in colon carcinoma hepatic metastasis was assessed using Kaplan-Meier survival analysis and log-rank tests. Positive expression of FRZB was correlated with liver metastasis of colon cancer. Univariate analysis indicated significantly worse overall survival (OS) for patients with a positive FRZB expression in colon carcinoma hepatic metastasis than for patients with a negative FRZB expression. Multivariate analysis showed positive-FRZB in colon carcinoma hepatic metastasis to be an independent prognostic factor for OS after hepatic resection (P = 0.001). Positive expression of FRZB was statistically significantly associated with poor prognosis of patients with colon carcinoma hepatic metastasis. FRZB could be a novel predictor for poor prognosis of patients with colon carcinoma hepatic metastasis after hepatic resection.     

Mesenchymal stem cells suppress lung inflammation and airway remodeling in chronic asthma rat model via PI3K/Akt signaling pathway

Background: Mesenchymal stem cells (MSCs) came out to attract wide attention and had become one of the hotspots of most diseases’ research in decades. But at present, the mechanisms of how MSCs work on chronic asthma remain undefined. Our study aims at verifying whether MSCs play a role in preventing inflammation and airway remodeling via PI3K/AKT signaling pathway in the chronic asthma rats model. Methods: First, an ovalbumin (OVA)-induced asthma model was built. MSCs were administered to ovalbumin-induced asthma rats. The total cells in a bronchial alveolar lavage fluid (BALF) and inflammatory mediators in BALF and serum were measured. Histological examination of lung tissue was performed to estimate the pathological changes. Additionally, the expression of phosphorylated-Akt (p-Akt) in all groups was measured by western blot and immunohistochemistry (IHC). Results: Compared to normal control group, the degree of airway inflammation and airway remodeling was significantly increased in asthma group. On the contrary, they were obviously inhibited in MSCs transplantation group. Moreover, the expression of p-Akt was increased in lung tissues of asthmatic rats, and suppressed by MSCs transplantation. Conclusion: Our results demonstrated that MSCs transplantation could suppress lung inflammation and airway remodeling via PI3K/Akt signaling pathway in rat asthma model.     

Preclinical Characterization and In Vivo Efficacy of GSK8853, a Small-Molecule Inhibitor of the Hepatitis C Virus NS4B Protein

The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit in vivo efficacy. We describe here the in vitro and in vivo antiviral activity of GSK8853, an imidazo[1,2-a]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed in vitro resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day in vitro treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates. In vivo efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of in vivo treatment revealed resistance mutations encoding amino acid changes that had not been identified by in vitro studies, including NS4B N56I and N99H. Our findings provide an in vivo proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.