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1.  Magnetic resonance elastography of the human abdominal aorta: a preliminary study 
Journal of magnetic resonance imaging : JMRI  2013;38(6):10.1002/jmri.24056.
Purpose
To investigate the feasibility of using magnetic resonance elastography (MRE) for the evaluation of the stiffness of in vivo aortic wall.
Materials and Methods
To validate the experimental approach for imaging the aorta in vivo, a gel phantom with an embedded porcine aorta was imaged in the presence of fluid flow within the aorta. The potential changes in the elasticity of the vessel wall with changes in pressure were investigated. The feasibility of performing MRE of abdominal aorta was assessed in five volunteers (Age 22–40 years; BMI 21.5–25.2 kg/m2). The pulse-gated cine MRE technique was used to study the wave propagation along the aorta throughout the cardiac cycle and provide estimates of aortic stiffness in diastole.
Results
In the phantom study, the wave propagation was well visualized within the porcine aorta embedded in the gel phantom. An increase of the Young's modulus-wall thickness (E*t) product with the increase in static pressure was observed. In the in vivo study, the waves were well visualized within the lumen of abdominal aorta in the five volunteers in diastolic phase, but they were not well visualized during systole.
Conclusion
MRE is feasible for noninvasively assessing the stiffness of the abdominal aorta and merits further investigation.
doi:10.1002/jmri.24056
PMCID: PMC3652910  PMID: 23371244
MRI; elastography; aorta; stiffness
2.  Hepatic and Splenic Stiffness Augmentation Assessed with MR Elastography in an in vivo Porcine Portal Hypertension Model 
Purpose
To investigate the influence of portal pressure on the shear stiffness of the liver and spleen in a well-controlled in vivo porcine model with MR Elastography (MRE). A significant correlation between portal pressure and tissue stiffness could be used to noninvasively assess increased portal venous pressure (portal hypertension), which is a frequent clinical condition caused by cirrhosis of the liver and is responsible for the development of many lethal complications.
Materials and Methods
During multiple intra-arterial infusions of Dextran-40 in three adult domestic pigs in vivo, 3-D abdominal MRE was performed with left ventricle and portal catheters measuring blood pressure simultaneously. Least-squares linear regressions were used to analyze the relationship between tissue stiffness and portal pressure.
Results
Liver and spleen stiffness have a dynamic component that increases significantly following an increase in portal or left ventricular pressure. Correlation coefficients with the linear regressions between stiffness and pressure exceeded 0.8 in most cases.
Conclusion
The observed stiffness-pressure relationship of the liver and spleen could provide a promising noninvasive method for assessing portal pressure. Using MRE to study the tissue mechanics associated with portal pressure may provide new insights into the natural history and pathophysiology of hepatic diseases and may have significant diagnostic value in the future.
doi:10.1002/jmri.24049
PMCID: PMC3661694  PMID: 23418135
MR Elastography; liver; spleen; portal pressure; shear stiffness
3.  A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped-Yorkie activity 
Cell Research  2013;23(10):1201-1214.
The Hippo (Hpo) pathway controls tissue growth and organ size by regulating the activity of transcriptional co-activator Yorkie (Yki), which associates with transcription factor Scalloped (Sd) in the nucleus to promote downstream target gene expression. Here we identify a novel protein Sd-Binding-Protein (SdBP)/Tgi, which directly competes with Yki for binding to Sd through its TDU domains and inhibits the Sd-Yki transcriptional activity. We also find that SdBP retains Yki in the nucleus through the association with Yki WW domains via its PPXY motifs. Collectively, we identify SdBP as a novel component of the Hpo pathway, negatively regulating the transcriptional activity of Sd-Yki to restrict tissue growth.
doi:10.1038/cr.2013.120
PMCID: PMC3790236  PMID: 23999857
Hippo; Sd
4.  Isolation and characterization of a Sca-1+/CD31- progenitor cell lineage derived from mouse heart tissue 
BMC Biotechnology  2014;14:75.
Background
Myocardial infarction remains the leading cause of mortality in developed countries despite recent advances in its prevention and treatment. Regenerative therapies based on resident cardiac progenitor cells (CPCs) are a promising alternative to conventional treatments. However, CPCs resident in the heart are quite rare. It is unclear how these CPCs can be isolated and cultured efficiently and what the effects of long-term culture in vitro are on their ‘stemness’ and differentiation potential, but this is critical knowledge for CPCs’ clinical application.
Results
Here, we isolated stem cell antigen-1 positive cells from postnatal mouse heart by magnetic active cell sorting using an iron-labeled anti-mouse Sca-1 antibody, and cultured them long-term in vitro. We tested stemness marker expression and the proliferation ability of long-term cultured Sca-1+ cells at early, middle and late passages. Furthermore, we determined the differentiation potential of these three passages into cardiac cell lineages (cardiomyocytes, smooth muscle and endothelial cells) after induction in vitro. The expression of myocardial, smooth muscle and endothelial cell-specific genes and surface markers were analyzed by RT-PCR and IF staining. We also investigated the oncogenicity of the three passages by subcutaneously injecting cells in nude mice. Overall, heart-derived Sca-1+ cells showed CPC characteristics: long-term propagation ability in vitro, non-tumorigenic in vivo, persistent expression of stemness and cardiac-specific markers, and multipotent differentiation into cardiac cell lineages.
Conclusions
Our research may bring new insights to myocardium regeneration, for which even a small number of biopsy-derived CPCs could be enriched and propagated long term in vitro to obtain sufficient seed cells for cell injection or cardiac tissue engineering.
doi:10.1186/1472-6750-14-75
PMCID: PMC4133720  PMID: 25106452
Cardiac progenitor cell; Stem cell antigen-1; Differentiation; Multipotent; Self-renewal
5.  Automated Liver Stiffness Measurements with Magnetic Resonance Elastography 
Purpose
To provide a fully-automated algorithm for obtaining stiffness measurements from hepatic MR Elastography images that are consistent with measurements performed by expert readers.
Materials and Methods
An initial liver contour was found using an adaptive threshold and expanded using an active contour to select a homogeneous area of the liver. The confidence map generated during the stiffness calculation was used to select a region of reliable wave propagation. The average stiffness within the automatically-generated ROI was compared to measurements by two trained readers in a set of 88 clinical test cases ranging from healthy to severely fibrotic.
Results
The stiffness measurements reported by the readers differed by −6.76% ± 22.8 % (95% confidence) and had an ICC of 0.972 (p<0.05).The algorithm and the more experienced reader differed by 4.32% ± 14.9 with an ICC of 0.987.
Conclusion
The automated algorithm performed reliably, even though MRE acquisitions often have motion artifacts present. The correlation between the automated measurements and those from the trained readers was superior to the correlation between the readers.
doi:10.1002/jmri.23980
PMCID: PMC3620931  PMID: 23281171
MR Elastography; Liver; Automation; Segmentation; Hepatic Fibrosis
6.  Magnetic Resonance Elastography of Liver: Clinical Applications 
Magnetic resonance elastography (MRE) has been successfully implemented in the assessment of diffuse liver diseases. Currently, MRE is the most accurate noninvasive technique for detection and staging of liver fibrosis with a potential to replace liver biopsy. Magnetic resonance elastography is able to differentiate isolated fatty liver disease from steatohepatitis with or without fibrosis. Potential clinical applications include the differentiation of benign and malignant focal liver masses and the assessment of treatment response in diffuse liver diseases.
doi:10.1097/RCT.0000000000000032
PMCID: PMC4075049  PMID: 24270110
magnetic resonance elastography; clinical applications; diffuse liver diseases; liver fibrosis; focal lesions; treatment response
7.  Electrospun gelatin/PCL and collagen/PLCL scaffolds for vascular tissue engineering 
Electrospun hybrid nanofibers prepared using combinations of natural and synthetic polymers have been widely investigated in cardiovascular tissue engineering. In this study, electrospun gelatin/polycaprolactone (PCL) and collagen/poly(l-lactic acid-co-ε-caprolactone) (PLCL) scaffolds were successfully produced. Scanning electron micrographs showed that fibers of both membranes were smooth and homogeneous. Water contact angle measurements further demonstrated that both scaffolds were hydrophilic. To determine cell attachment and migration on the scaffolds, both hybrid scaffolds were seeded with human umbilical arterial smooth muscle cells. Scanning electron micrographs and MTT assays showed that the cells grew and proliferated well on both hybrid scaffolds. Gross observation of the transplanted scaffolds revealed that the engineered collagen/PLCL scaffolds were smoother and brighter than the gelatin/PCL scaffolds. Hematoxylin and eosin staining showed that the engineered blood vessels constructed by collagen/PLCL electrospun membranes formed relatively homogenous vessel-like tissues. Interestingly, Young’s modulus for the engineered collagen/PLCL scaffolds was greater than for the gelatin/PCL scaffolds. Together, these results indicate that nanofibrous collagen/PLCL membranes with favorable mechanical and biological properties may be a desirable scaffold for vascular tissue engineering.
doi:10.2147/IJN.S61375
PMCID: PMC4026554  PMID: 24872696
electrospinning; gelatin; collagen; polycaprolactone; poly(l-lactic acid-co-ε-caprolactone)
8.  Magnetic Resonance Elastography of Liver: Technique, Analysis and Clinical Applications 
Many pathological processes cause marked changes in the mechanical properties of tissue. Magnetic Resonance Elastography (MRE) is a non-invasive MRI based technique for quantitatively assessing the mechanical properties of tissues in vivo. MRE is performed by using a vibration source to generate low frequency mechanical waves in tissue, imaging the propagating waves using a phase contrast MRI technique, and then processing the wave information to generate quantitative images showing mechanical properties such as tissue stiffness. Since its first description in 1995, published studies have explored many potential clinical applications including brain, thyroid, lung, heart, breast, and skeletal muscle imaging. However, the best-documented application to emerge has been the use of MRE to assess liver disease. Multiple studies have demonstrated that there is a strong correlation between MRE-measured hepatic stiffness and the stage of fibrosis at histology. The emerging literature indicates that MRE can serve as a safer, less expensive, and potentially more accurate alternative to invasive liver biopsy which is currently the gold standard for diagnosis and staging of liver fibrosis. This review describes the basic principles, technique of performing a liver MRE, analysis and calculation of stiffness, clinical applications, limitations, and potential future applications.
doi:10.1002/jmri.23731
PMCID: PMC3579218  PMID: 23423795
Magnetic Resonance Elastography (MRE); Liver; Fibrosis; Technique; Analysis; Clinical applications
9.  Brahma is essential for Drosophila intestinal stem cell proliferation and regulated by Hippo signaling 
eLife  2013;2:e00999.
Chromatin remodeling processes are among the most important regulatory mechanisms in controlling cell proliferation and regeneration. Drosophila intestinal stem cells (ISCs) exhibit self-renewal potentials, maintain tissue homeostasis, and serve as an excellent model for studying cell growth and regeneration. In this study, we show that Brahma (Brm) chromatin-remodeling complex is required for ISC proliferation and damage-induced midgut regeneration in a lineage-specific manner. ISCs and enteroblasts exhibit high levels of Brm proteins; and without Brm, ISC proliferation and differentiation are impaired. Importantly, the Brm complex participates in ISC proliferation induced by the Scalloped–Yorkie transcriptional complex and that the Hippo (Hpo) signaling pathway directly restricted ISC proliferation by regulating Brm protein levels by inducing caspase-dependent cleavage of Brm. The cleavage resistant form of Brm protein promoted ISC proliferation. Our findings highlighted the importance of Hpo signaling in regulating epigenetic components such as Brm to control downstream transcription and hence ISC proliferation.
DOI: http://dx.doi.org/10.7554/eLife.00999.001
eLife digest
Most tissues can generate new cells to repair damage or replace worn-out cells. The new cells are often generated from stem cells—cells that can either reproduce themselves or mature into other types of cells. In the fruit-fly Drosophila, for example, intestinal stem cells in the midgut are capable of producing more stem cells or they can differentiate to produce immature cells called enteroblasts that go on to become either enterocytes (the cells that line the gut) or enteroendocrine cells (which secrete hormones).
Researchers have identified a number of signalling pathways that are involved in the proliferation and differentiation of intestinal stem cells in the midgut of fruit flies. These include the Hippo pathway, which is important for regulating both cell proliferation and programmed cell death (apoptosis). Activation of the Hippo protein triggers a cascade of signals that culminate in the regulation of many of the genes involved in cell proliferation, division and apoptosis.
Another process that is important for controlling the proliferation and differentiation of cells is chromatin remodelling. Chromatin is the ‘packaging’ that keeps DNA tightly wound within the cell nucleus, and remodelling refers to the structural changes that allow proteins called transcription factors to reach the genes and transcribe them into messenger RNA (which then leaves the nucleus to generate the protein).
Now, Jin et al. have explored how the Hippo pathway and chromatin remodelling work together to regulate of stem cells. Using a technique called RNA interference to block the expression of various genes in intestinal stem cells and enteroblasts, Jin et al. found that a protein called Brahma—which is an essential part of a chromatin-remodelling complex—must be present for the stem cells to multiply normally.
Jin et al. also showed how the Hippo signalling pathway interacts with chromatin remodelling. Activation of the Hippo pathway inhibits gene expression by preventing two other proteins, Yorkie and Scalloped, from forming a complex in the nucleus. The new work shows that Brahma interacts physically with the Yorkie and Scalloped proteins to regulate the proliferation of the intestinal stem cells. It also shows that the Hippo protein regulates the activity of the Brahma protein by inducing a process called caspase-dependent cleavage. Because many of the proteins involved in these pathways are evolutionarily conserved and expressed in a variety of tissues, these findings may have implications for stem cell function and tissue repair in many species.
DOI: http://dx.doi.org/10.7554/eLife.00999.002
doi:10.7554/eLife.00999
PMCID: PMC3796317  PMID: 24137538
Hippo signaling; brahma; midgut; D. melanogaster
10.  Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment 
Cancer research  2012;72(16):4047-4059.
The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin (FN) that promote α5β1 integrin-dependent FN fibril assembly, matrix stiffness, and tumor growth. Tumor growth and FN fibril assembly was reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in FN fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl, that augmented α5β1 FN fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of FN fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment.
doi:10.1158/0008-5472.CAN-11-3907
PMCID: PMC3421041  PMID: 22738912
Fibronectin; Integrin; Neuropilin; Matrix; Myofibroblast
11.  Par-1 Regulates Tissue Growth by Influencing Hippo Phosphorylation Status and Hippo-Salvador Association 
PLoS Biology  2013;11(8):e1001620.
Par-1 regulates the Hippo signaling pathway in Drosophila melanogaster by modifying the phosphorylation status of Hippo and also by inhibiting the interaction of Hippo and Salvador.
The evolutionarily conserved Hippo (Hpo) signaling pathway plays a pivotal role in organ size control by balancing cell proliferation and cell death. Here, we reported the identification of Par-1 as a regulator of the Hpo signaling pathway using a gain-of-function EP screen in Drosophila melanogaster. Overexpression of Par-1 elevated Yorkie activity, resulting in increased Hpo target gene expression and tissue overgrowth, while loss of Par-1 diminished Hpo target gene expression and reduced organ size. We demonstrated that par-1 functioned downstream of fat and expanded and upstream of hpo and salvador (sav). In addition, we also found that Par-1 physically interacted with Hpo and Sav and regulated the phosphorylation of Hpo at Ser30 to restrict its activity. Par-1 also inhibited the association of Hpo and Sav, resulting in Sav dephosphorylation and destabilization. Furthermore, we provided evidence that Par-1-induced Hpo regulation is conserved in mammalian cells. Taken together, our findings identified Par-1 as a novel component of the Hpo signaling network.
Author Summary
An organism's organ size is determined by cell number, the size of each cell, and the distance between cells. All of these factors are controlled by the coordination of different cell signaling pathways and other mechanisms. The Hippo signaling pathway controls organ size by restricting the number of cells that make up the organ. Malfunction of this pathway leads to abnormal overgrowth, and is involved in a large number of human diseases and cancers. We identify here a component of the Hippo pathway, Par-1, which controls tissue growth by negatively regulating the Hippo pathway. We show that overexpression or depletion of Par-1 influences tissue growth in fruit flies via Hippo signaling. Then, by genetic and biochemical experiments, we show that Par-1 interacts with Hippo, regulating the Hippo Ser30 phosphorylation status to alter Hippo activity. In addition, we found that Par-1 regulates Hippo signaling via inhibition of the Hippo-Salvador association in a kinase-dependent fashion. We predict that Par-1 is a potential oncogene and that its regulatory role in Hippo signaling could be conserved.
doi:10.1371/journal.pbio.1001620
PMCID: PMC3735459  PMID: 23940457
13.  Pediatric MR elastography of hepatic fibrosis: principles, technique and early clinical experience 
Pediatric Radiology  2011;42(4):402-409.
Summary
MR elastography is one of the only non-invasive techniques that can accurately and reliably identify and stage liver fibrosis. Importantly, it has been shown to more effectively stage liver fibrosis in adults than other non-invasive assessments and thus can be used to follow treatment response or disease progression. The mechanical properties of liver tissue appear to be the same for adults and children suggesting MRE will prove to be an accurate non-invasive test for identifying, staging and tracking liver fibrosis. In our experience it is technically feasible for pediatric patients, even in young infants. MRE findings appear to correlate well with liver biopsy results in the small number of patients where we have pathologic correlation but larger, studies will be needed to confirm the reliability and accuracy of this technique to establish it as an alternative to pediatric liver biopsy.
doi:10.1007/s00247-011-2298-6
PMCID: PMC3352031  PMID: 22120578
14.  Assessment of stiffness changes in the ex vivo porcine aortic wall using magnetic resonance elastography 
Magnetic resonance imaging  2011;30(1):122-127.
Magnetic resonance elastography (MRE) is a noninvasive phase-contrast technique for estimating the mechanical properties of tissues by imaging propagating mechanical waves within the tissue. In this study, we hypothesize that changes in arterial wall stiffness, experimentally induced by formalin fixation, can be measured using MRE in ex vivo porcine aortas. In agreement with our hypothesis, the significant stiffness increase after sample fixation were clearly demonstrated by MRE and confirmed by mechanical testing. The results indicate that MRE can be used to examine the stiffness changes of the aorta. This study has provided evidence of the effectiveness of using MRE to directly assess the stiffness change in aortic wall. The results offer motivation to pursue MRE as a noninvasive method for the evaluation of arterial wall mechanical properties.
doi:10.1016/j.mri.2011.09.009
PMCID: PMC3238136  PMID: 22055848
MRI; Elastography; Aorta; Stiffness
15.  Bias Observed in Time-of-flight Shear Wave Speed Measurements Using Radiation Force of a Focused Ultrasound Beam 
Ultrasound in medicine & biology  2011;37(11):1884-1892.
Measurement of shear wave propagation speed has important clinical applications because it is related to tissue stiffness and health state. Shear waves can be generated in tissues by the radiation force of a focused ultrasound beam (push beam). Shear wave speed can be measured by tracking its propagation laterally from the push beam focus using the time-of-flight principle. This study shows that shear wave speed measurements with such methods can be transducer, depth, and lateral tracking range dependent. Three homogeneous phantoms with different stiffness were studied using curvilinear and linear array transducer. Shear wave speed measurements were made at different depths, using different aperture sizes for push, and at different lateral distance ranges from the push beam. The curvilinear transducer shows a relatively large measurement bias that is depth dependent. The possible causes of the bias and options for correction are discussed. These bias errors must be taken into account to provide accurate and precise time-of-flight shear wave speed measurements for clinical use.
doi:10.1016/j.ultrasmedbio.2011.07.012
PMCID: PMC3199321  PMID: 21924817
Shear wave speed; Liver fibrosis; Bias; ARFI
16.  Test-Retest Repeatability of Magnetic Resonance Elastography for Non-Invasive Liver Fibrosis Assessment in Hepatitis C 
Purpose
To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by magnetic resonance elastography (MRE) in healthy and hepatitis-C infected subjects.
Materials and Methods
A biopsy-correlated repeatability study using 4-slice MRE was conducted in 5 healthy and 4 HCV-infected subjects. Subjects were scanned twice on day 1 and after 7 – 14 days. Each slice was acquired during a 14 second breath-hold with a commercially available acquisition technique (MR-Touch, GE Healthcare). Results were analyzed by two independent analysts.
Results
The intraclass correlation coefficient (ICC) was 0.85 (90% CI: 0.71 to 0.98) for the between-scan average of maximum stiffness within each slice and 0.88 (90% CI: 0.78 to 0.99) for the average of mean stiffness within each slice for the primary analyst. For both analysts, the average of the mean liver stiffness within each slice was highly reproducible with ICC of 0.93 and 0.94. Within-subject coefficients of variation ranged from 6.07% to 10.78% for HCV+ and healthy subjects.
Conclusion
MRE is a highly reproducible modality for assessing liver stiffness in HCV patients and healthy subjects and can discriminate between moderate fibrosis and healthy liver. MRE is a promising modality for non-invasive assessment of liver fibrosis. (Clinicaltrials.gov identifier: NCT00896233)
doi:10.1002/jmri.22716
PMCID: PMC3176946  PMID: 21751289
MRE; elastic modulus; hepatitis C; fibrosis
17.  Noninvasive in vivo assessment of renal tissue elasticity during graded renal ischemia using MR Elastography 
Investigative radiology  2011;46(8):509-514.
Objectives
Magnetic Resonance Elastography (MRE) allows noninvasive assessment of tissue stiffness in vivo. Renal arterial stenosis (RAS), a narrowing of the renal artery, promotes irreversible tissue fibrosis that threatens kidney viability and may elevate tissue stiffness. However, kidney stiffness may also be affected by hemodynamic factors. This study tested the hypothesis that renal blood flow (RBF) is an important determinant of renal stiffness as measured by MRE.
Material and Methods
In six anesthetized pigs MRE studies were performed to determine cortical and medullary elasticity during acute graded decreases in RBF (by 20, 40, 60, 80, and 100% of baseline) achieved by a vascular occluder. Three sham-operated swine served as time control. Additional pigs were studied with MRE six weeks after induction of chronic unilateral RAS (n=6) or control (n=3). Kidney fibrosis was subsequently evaluated histologically by trichrome staining.
Results
During acute RAS the stenotic cortex stiffness decreased (from 7.4 ± 0.3 to 4.8 ± 0.6 kPa, p=0.02 vs. baseline) as RBF decreased. Furthermore, in pigs with chronic RAS (80±5.4% stenosis) in which RBF was decreased by 60±14% compared to controls, cortical stiffness was not significantly different from normal (7.4 ± 0.3 vs. 7.6 ± 0.3 kPa, p=0.3), despite histological evidence of renal tissue fibrosis.
Conclusion
Hemodynamic variables modulate kidney stiffness measured by MRE and may mask the presence of fibrosis. These results suggest that kidney turgor should be considered during interpretation of elasticity assessments.
doi:10.1097/RLI.0b013e3182183a95
PMCID: PMC3128234  PMID: 21467945
MR Elastography; MRI; kidney; stiffness
18.  PORTAL HYPERTENSION CORRELATES WITH SPLENIC STIFFNESS AS MEASURED WITH MAGNETIC RESONANCE ELASTOGRAPHY 
Purpose
To investigate the correlation between MRE assessed spleen stiffness and direct portal vein pressure gradient (D-HVPG) measurements in a large animal model of portal hypertension.
Materials and Methods
Cholestatic liver disease was established in adult canines by common bile duct ligation. A spin echo based EPI MRE sequence was used to acquire 3-D/3-axis abdominal MRE data at baseline, four weeks, and eight weeks. Liver biopsies, blood samples, and D-HVPG measurements were obtained simultaneously.
Results
Animals developed portal hypertension (D-HVPG: 11.0±5.1 mmHg) with only F1 fibrosis after four weeks. F3 fibrosis was confirmed after eight weeks despite no further rise in portal hypertension (D-HVPG: 11.3±3.2 mmHg). Mean stiffnesses of the spleen increased over two-fold from baseline (1.72±0.33 kPa) to four weeks (3.54±0.31 kPa), and stabilized at eight weeks (3.38±0.06 kPa) in a pattern consistent with changes in portal pressure. A positive correlation was observed between spleen stiffness and D-HVPG (r2 = 0.86, p<0.01).
Conclusion
These findings indicate a temporal relationship between portal hypertension and the development of liver fibrosis in a large animal model of cholestatic liver disease. The observed direct correlation between spleen stiffness and D-HVPG suggest a non-invasive MRE approach to diagnose and screen for portal hypertension.
doi:10.1002/jmri.22610
PMCID: PMC3121904  PMID: 21608066
Magnetic Resonance Elastography; Portal Hypertension; Spleen Stiffness; HVPG; Cirrhosis
19.  Effects of polymer molecular weight on relative oral bioavailability of curcumin 
Background
Polylactic-co-glycolic acid (PLGA) nanoparticles have been used to increase the relative oral bioavailability of hydrophobic compounds and polyphenols in recent years, but the effects of the molecular weight of PLGA on bioavailability are still unknown. This study investigated the influence of polymer molecular weight on the relative oral bioavailability of curcumin, and explored the possible mechanism accounting for the outcome.
Methods
Curcumin encapsulated in low (5000–15,000) and high (40,000–75,000) molecular weight PLGA (LMw-NPC and HMw-NPC, respectively) were prepared using an emulsification-solvent evaporation method. Curcumin alone and in the nanoformulations was administered orally to freely mobile rats, and blood samples were collected to evaluate the bioavailability of curcumin, LMw-NPC, and HMw-NPC. An ex vivo experimental gut absorption model was used to investigate the effects of different molecular weights of PLGA formulation on absorption of curcumin. High-performance liquid chromatography with diode array detection was used for quantification of curcumin in biosamples.
Results
There were no significant differences in particle properties between LMw-NPC and HMw-NPC, but the relative bioavailability of HMw-NPC was 1.67-fold and 40-fold higher than that of LMw-NPC and conventional curcumin, respectively. In addition, the mean peak concentration (Cmax) of conventional curcumin, LMw-NPC, and HMw-NPC was 0.028, 0.042, and 0.057 μg/mL, respectively. The gut absorption study further revealed that the HMw-PLGA formulation markedly increased the absorption rate of curcumin in the duodenum and resulted in excellent bioavailability compared with conventional curcumin and LMw-NPC.
Conclusion
Our findings demonstrate that different molecular weights of PLGA have varying bioavailability, contributing to changes in the absorption rate at the duodenum. The results of this study provide the rationale for design of a nanomedicine delivery system to enhance the bioavailability of water-insoluble pharmaceutical compounds and functional foods.
doi:10.2147/IJN.S32630
PMCID: PMC3384366  PMID: 22745556
absorption; duodenum; molecular weight; poly(lactic-co-glycolic acid); PLGA; relative oral bioavailability
20.  Cuprous oxide nanoparticles selectively induce apoptosis of tumor cells 
In the rapid development of nanoscience and nanotechnology, many researchers have discovered that metal oxide nanoparticles have very useful pharmacological effects. Cuprous oxide nanoparticles (CONPs) can selectively induce apoptosis and suppress the proliferation of tumor cells, showing great potential as a clinical cancer therapy. Treatment with CONPs caused a G1/G0 cell cycle arrest in tumor cells. Furthermore, CONPs enclosed in vesicles entered, or were taken up by mitochondria, which damaged their membranes, thereby inducing apoptosis. CONPs can also produce reactive oxygen species (ROS) and initiate lipid peroxidation of the liposomal membrane, thereby regulating many signaling pathways and influencing the vital movements of cells. Our results demonstrate that CONPs have selective cytotoxicity towards tumor cells, and indicate that CONPs might be a potential nanomedicine for cancer therapy.
doi:10.2147/IJN.S31133
PMCID: PMC3368515  PMID: 22679374
nanomedicine; selective cytotoxicity; apoptosis; cell cycle arrest; mitochondrion-targeted nanomaterials
21.  Liver Stiffness Measurement by Magnetic Resonance Elastography is not associated with Developing Hepatocellular Carcinoma in Subjects with Compensated Cirrhosis 
Background
Liver stiffness assessed by transient elastography is described as a potential risk factor for hepatocellular carcinoma (HCC) in cirrhosis. However, the strict assessment of hepatic parenchymal areas uninvolved with HCC has not been investigated.
Aims
To determine if liver stiffness of non-malignant hepatic parenchyma by MR elastography (MRE) is higher in patients with HCC compared to controls.
Methods
Cases were defined by compensated cirrhosis with a Child-Turcotte-Pugh (CTP) score < 7 and HCC by radiological criteria or histology. Control subjects with compensated cirrhosis were frequency matched to cases by sex and disease etiology. Overt manifestations of portal hypertension and previous therapy for liver disease or HCC were exclusion criteria. Region of interest analyses were performed on hepatic parenchyma regions distant to HCC location among cases.
Results
30 patients with HCC and 60 matched controls comprised the study cohort. The mean age for cases was 64 ± 10 years (range, 45–85) with 70% men. Major disease etiologies were chronic viral hepatitis (57%), nonalcoholic fatty liver disease (33%), and alcohol (10%). Twenty-eight (93%) patients had solitary HCC lesions with a mean size of 5.2 cm (range, 2–14 cm). However, patients with HCC had similar liver stiffness among uninvolved areas distant to HCC lesions as compared to controls without HCC (mean, 6.1±2.0 kPa vs. mean, 6.3 ± 2.5 kPa, p=0.7).
Conclusion
In contrast to previous studies with transient elastography, we did not observe a systematic association between liver stiffness assessed by MRE and the presence of HCC in patients with compensated cirrhosis.
doi:10.1111/j.1365-2036.2011.04673.x
PMCID: PMC3269836  PMID: 21535445
22.  Dynamic Postprandial Hepatic Stiffness Augmentation Assessed With MR Elastography in Patients With Chronic Liver Disease 
Objective
MR elastography (MRE) is an MRI-based technique for quantitatively assessing tissue stiffness by studying shear wave propagation through tissue. The goal of this study was to test the hypothesis that hepatic MRE performed before and after a meal will result in a postprandial increase in hepatic stiffness among patients with hepatic fibrosis because of transiently increased portal pressure.
Subjects and Methods
Twenty healthy volunteers and 25 patients with biopsy-proven hepatic fibrosis were evaluated. Preprandial MRE measurements were performed after overnight fasting. A liquid test meal was administered, and 30 minutes later a postprandial MRE acquisition was performed. Identical imaging parameters and analysis regions of interest were used for pre- and postprandial acquisitions.
Results
The results in the 20 subjects without liver disease showed a mean stiffness change of 0.16 ± 0.20 kPa (range, −0.12 to 0.78 kPa) or 8.08% ± 10.33% (range, −5.36% to 41.7%). The hepatic stiffness obtained in the 25 patients with hepatic fibrosis showed a statistically significant increase in postprandial liver stiffness, with mean augmentation of 0.89 ± 0.96 kPa (range, 0.17–4.15 kPa) or 21.24 ± 14.98% (range, 7.69%–63.3%).
Conclusion
MRE-assessed hepatic stiffness elevation in patients with chronic liver disease has two major components: a static component reflecting structural change or fibrosis and a dynamic component reflecting portal pressure that can increase after a meal. These findings will provide motivation for further studies to determine the potential value of assessing postprandial hepatic stiffness augmentation for predicting the progression of fibrotic disease and the development of portal hypertension. The technique may also provide new insights into the natural history and pathophysiology of chronic liver disease.
doi:10.2214/AJR.10.5989
PMCID: PMC3151663  PMID: 21701012
hepatic stiffness; MR elastography; perfusion; postprandial augmentation
23.  Abdominal MR Elastography 
MR Elastography (MRE) is an MRI-based technique for quantitatively assessing the mechanical properties of tissues, based on the propagation of shear waves. Multiple studies have described many potential applications of MRE, from characterizing tumors to detecting diffuse disease processes. Studies have shown that MRE can be successfully implemented to assess abdominal organs. The first clinical application MRE to be well documented is the detection and characterization of hepatic fibrosis, which systematically increases the stiffness of liver tissue. In this diagnostic role, offers a safer, and less expensive, and potentially more accurate alternative to invasive liver biopsy. Emerging results suggest that measurements of liver and spleen stiffness may provide an indirect way to assess portal hypertension. Preliminary studies have demonstrated that is possible to use MRE to evaluate the mechanical properties of other abdominal structures, such as the pancreas and kidneys. Steady technical progress in developing practical protocols for applying MRE in the abdomen and pelvis provides opportunities to explore many other potential applications of this emerging technology.
doi:10.1097/RMR.0b013e3181c4737e
PMCID: PMC3068842  PMID: 20010062
Abdominal MR Elastography; MRI
24.  High-Frequency Mode Conversion Technique for Stiff Lesion Detection with Magnetic Resonance Elastography 
A novel imaging technique is described in which the mode conversion of longitudinal waves is used for the qualitative detection of stiff lesions within soft tissue using Magnetic Resonance Elastography (MRE) methods. Due to the viscoelastic nature of tissue, high-frequency shear waves attenuate rapidly in soft tissues but much less in stiff tissues. By introducing minimally attenuating longitudinal waves at a significantly high frequency into tissue, shear waves produced at interfaces by mode conversion will be detectable in stiff regions, but will be significantly attenuated and thus not detectable in the surrounding soft tissue. This contrast can be used to detect the presence of stiff tissue. The proposed technique is shown to readily depict hard regions (mimicking tumors) present in tissue-simulating phantoms and ex vivo breast tissue. In vivo feasibility is demonstrated on a patient with liver metastases where the tumors are readily distinguished. Preliminary evidence also suggests that quantitative stiffness measurements of stiff regions obtained with this technique are more accurate than those from conventional MRE because of the short shear wavelengths. This rapid, qualitative technique may lend itself to applications in which the localization of stiff, suspicious neoplasms is coupled with more sensitive techniques for thorough characterization.
doi:10.1002/mrm.22091
PMCID: PMC3027306  PMID: 19859936
MR Elastography; high-frequency MRE; mode conversion; stiff lesion detection; stiffness
25.  Magnetic Resonance Elastography of Liver Tumors- Preliminary Results 
AJR. American journal of roentgenology  2008;190(6):1534-1540.
Aim
To evaluate the potential value of magnetic resonance elastography (MRE) for characterizing solid liver tumors.
Materials and Methods
Forty-four liver tumors (metastases-14, hepatocellular carcinoma- 12, hemangioma-9, cholangiocarcinoma-5, focal nodular hyperplasia-3, and hepatic adenoma-1) were evaluated with MRE. MRE was performed on a 1.5 T scanner with a modified phase-contrast, gradient echo sequence to collect axial wave images sensitized along the through-plane motion direction. The tumors were identified in T2-, T1-weighted and gadolinium enhanced T1-weighted images and the MRE images were obtained through the tumor. A stiffness map (elastogram) was generated by an automated process using an inversion algorithm. The mean shear stiffness of the tumor was calculated using a manually specified region of interest placed over the tumor in the stiffness map. The stiffness value of non-tumor bearing hepatic parenchyma was also calculated. Statistical analysis was performed on the stiffness values for differentiation between normal liver, fibrotic liver, benign tumors and malignant tumors.
Results
Malignant liver tumors had significantly higher mean shear stiffness than benign tumors, fibrotic liver and normal liver (10.1kPa vs. 2.7kpa (p<0.001), vs. 5.9kPa (p<0.001) and vs. 2.3kPa (p<0.001) respectively). Fibrotic livers had stiffness values overlapping both the benign and malignant tumors. Cut-off values of 5kPa accurately differentiate malignant tumors from benign tumors and normal liver parenchyma in this preliminary investigation.
Conclusions
MR elastography is a promising, non-invasive technique for assessing solid liver tumors. MRE may provide new, quantitative tissue characterization parameters for differentiating benign and malignant liver tumors.
doi:10.2214/AJR.07.3123
PMCID: PMC2894569  PMID: 18492904

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