Effect of magnetic resonance imaging in liver metastases

This letter to the editor is a commentary on a study titled"Liver metastases:The role of magnetic resonance imaging."Exploring a noninvasive imaging evaluation system for the biological behavior of hepatocellular carcinoma(HCC)is the key to achieving precise diagnosis and treatment and improving prognosis.This review summarizes the role of magnetic resonance imaging in the detection and evaluation of liver metastases,describes its main imaging features,and focuses on the added value of the latest imaging tools(such as T1 weighted in phase imaging,T1 weighted out of phase imaging;diffusion-weighted imaging,T2 weighted imaging).In this study,I investigated the necessity and benefits of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid for HCC diagnostic testing and prognostic evaluation.

Liver-specific glucocorticoid action in alcoholic liver disease:Study of glucocorticoid receptor knockout and knockin mice

Background and aim:Glucocorticoids are the only first-line drugs for severe alcoholic hepatitis(AH),with limited efficacy and various side effects on extrahepatic tissues.Liver-targeting glucocorticoid therapy may have multiple advantages over systemic glucocorticoid for AH.The aim of this study was to determine the role of hepatocellular glucocorticoid receptor(GR)in alcohol-associated steatosis(AS)and AH.Materials and methods:AS was induced by a high-fat diet plus binge alcohol in adult male and female mice with liver-specific knockout(LKO)and heterozygote of GR.AH was induced by chronic-plus-binge in middle-aged male mice with liver-specific knockin of GR.Changes in hepatic mRNA and protein expression were determined by quantitative real-time polymerase chain reaction and Western blot.Results:GR-LKO aggravated steatosis and decreased hepatic expression and circulating levels of albumin in both genders of AS mice but only increased markers of liver injury in male AS mice.Marked steatosis in GR-LKO mice was associated with induction of lipogenic genes and down-regulation of bile acid synthetic genes.Hepatic protein levels of GR,hepatocyte nuclear factor 4 alpha,and phosphorylated signal transducer and activator of transcription 3 were gene-dosage-dependently decreased,whereas that of lipogenic ATP citrate lyase was increased in male GR heterozygote and LKO mice.Interestingly,hepatic expression of estrogen receptor alpha(ERα)was induced,and the essential estrogen-inactivating enzyme sulfotransferase 1e1 was gene-dosage-dependently down-regulated in GR heterozygote and knockout AS mice,which was associated with induction of ERα-target genes.Liver-specific knockin of GR protected against liver injury and steatohepatitis in middle-aged AH mice.Conclusions:Hepatic GR deficiency plays a crucial role in the pathogenesis of AS induced by high-fat diet plus binge,and liver-specific overexpression/activation of GR protects against chronic-plus-binge-induced AH in middle-aged mice.Hepatocellular GR is important for protection against AS and AH.

Gadoxetic acid-enhanced magnetic resonance imaging for the detection of small hepatocellular carcinoma(≤ 2.0 cm) in patients with chronic liver disease:A meta-analysis

AIM To perform a meta-analysis assessing the value of gadoxetic acid-enhanced magnetic resonance imaging(Gd-EOB-MRI)in detecting small hepatocellular carcinoma(HCC)(≤2.0 cm)in patients with chronic liver disease.METHODS Databases,including MEDLINE and EMBASE,were searched for relevant original articles published from January 2008 to February 2015.Data were extracted,and summary estimates of diagnostic accuracy indexes such as sensitivity,specificity,diagnostic odds ratio,predictive value,and areas under summary receiver operating characteristic curve were obtained using a random-effects model,with further exploration employing meta-regression and subgroup analyses.RESULTS In 10 studies evaluating 768 patients,pooled perlesion sensitivity of Gd-EOB-DTPA was 91%(95%CI:83%-95%),with a specificity of 95%(95%CI:87%-98%).Overall positive likelihood ratio was 18.1(95%CI:6.6-49.4),for negative likelihood ratio(NLR)of 0.10(95%CI:0.05-0.19)and diagnostic odds ratio of182(95%CI:57-581).Subgroup analysis suggested that diagnostic performance of Gd-EOB-MRI for sub-centimeter HCC(≤1.0 cm)detection was low,with a sensitivity of69%(95%CI:59%-78%).In studies with both Gd-EOBMRI and diffusion-weighted imaging(DWI)performed,Gd-EOB-MRI/DWI combination was more sensitive than Gd-EOB-DTPA alone,whether for small lesions(86%vs77%)or sub-centimeter ones(80%vs 56%).CONCLUSION A limited number of small studies suggested that GdEOB-MRI has good diagnostic performance in the detection of small HCC(≤2.0 cm)among patients with chronic liver disease,but relatively lower performance for detection of sub-centimeter HCC(≤1.0 cm).Combination of Gd-EOB-MRI and DWI can improve the diagnostic sensitivity of MRI.

Novel liver-specific nitric oxide(NO) releasing drugs with bile acid as both NO carrier and targeting ligand

Novel liver-specific nitric oxide（NO） releasing drugs with bile acid as both the NO carrier and targeting ligand were designed and synthesized by direct nitration of the hydroxyl group in bile acids or the 3-Ohydroxyl alkyl derivatives,with the intact 24-COOH being preserved for hepatocyte specific recognition.Preliminary biological evaluation revealed that oral administrated targeted conjugates could protect mice against acute liver damage induced by acetaminophen or carbon tetrachloride.The nitrate level in the liver significantly increased after oral administration of 1e while nitrate level in the blood did not significantly change.Co-administration of ursodeoxycholic acid（UDCA） significantly antagonized the increase of nitrate in the liver resulted by administration of 1e.

Optimized human factor IX expression cassettes for hepaticdirected gene therapy of hemophilia B

Gene therapy provides a potential cure for hemophilia B, and significant progress has been achieved in liver-directed gene transfer mediated by adeno-associated viral vectors. Recent clinical trials involving the use of a self-complementary adeno-associated virus serotype 8-human codon-optimized factor IX （AAV8-hFIXco） vector demonstrated encouraging efficacy with hFIX expression stabilized at 1% to 6% of normal level in patients, but safety concerns related to high vector doses are still present. Thus, further improvement of AAV vectors and hFIX expression cassette may positively contribute to the ultimate success of hemophilia B gene therapy. In this study, to obtain a higher expression level of hFIX that potentiates the coagulant capacity of recipients, human FIX expression vector was optimized by upgrading the codon adaption index and adjusting the GC content, inserting a Kozak sequence （GCCACC）, and introducing a gain-of-function mutation, R338L （FIX Padua）. The efficiency of the published and the presently constructed cassettes was compared through in vivo screening. In addition, the regulatory elements that control the FIX gene expression in these cassettes were screened for liver-specific effectiveness. Among all the constructed cassettes, scAAV-Pre-hFIXco-SIH-R338L, which was the construct under the control of the prothrombin enhancer and prealbumin promoter, resulted in the highest level of coagulant activity, and the expression levels of two constructed cassettes （scAAV-Chi-hFIXco-SIH-R338L and scAAV-Pre- hFIXco-SIH-R338L） were also higher than that of the published cassette （scAAV-LPI-hFIXco-SJ）. In summary, our strategies led to a substantial increase in hFIX expression at the protein level or a remarkably elevated coagulant activity. Thus, these reconstructs of hFIX with AAV vector may potentially contribute to the creation of an efficacious gene therapy of hemophilia B.