Demographic histories can also be estimated from genealogies (phylogenies) in a Bayesian statistical framework using BEAST (versions 1.4.6 and 1.7.2, Drummond and Rambaut 2007; http://beast.bio.ed.ac.uk). MODELTEST (Posada and Crandall 1998), using the Akaike information criterion, indicated that the nucleotide substitution model of Hasegawa et al. (1985) was appropriate Natural Product Library cost when additionally allowing for unequal substitution rates among sites and for a proportion of sites to be invariable. When using BEAST, runs were of sufficient length

(typically 30 million or more) that effective sample sizes (ESSs) were always over 100, and usually very far over this value. Several runs were done for each input file to check for convergence. The program TRACER v1.4 (http://beast.bio.ed.ac.uk/) was used to analyze the output from BEAST. The first 10% of iterations in each run were discarded as burn-in. A coalescent exponential expansion model was specified and a randomWalkOperator selected for the exponential.growthRate parameter (Supplementary data files 2 and 3). If the 95% highest posterior density (HPD) of the growth rate parameter check details includes zero, a hypothesis of constant population size cannot be rejected (Marino et al. 2011; https://groups.google.com/d/msg/beast-users/y-ppM_dB5UI/uPybHlRMYc4J).

Monophyly of Australian dugongs was forced, and a prior of 115,000 yr (normal distribution ± 5,000) (date of the closure of Torres Strait to transit by marine organisms at the start of the last glacial period inferred from sea-level estimates; Fig. 2)

placed on the most Cyclin-dependent kinase 3 recent common ancestor (MRCA) of all Australian dugongs (see Supplementary data file 6). Trees generated during this analysis were examined for the strength of support given to the individual lineages. Bayesian skyline plots (BSPs) (Drummond et al. 2005) show changes in effective population size (NE(FEMALE)) over time, along with credibility intervals. A major advantage of this approach is that it avoids problems associated with choosing a single demographic scenario such as “constant population size” or “exponential growth.” Sample input files are in Supplementary data files 4 and 5. The mutation rate prior was specified (following the analysis above) as normally distributed with a mean of 24.8% per million years and lower and upper bounds of 13.89% and 37.46% per million years, respectively. Given that most samples came from distinct localities where sampling was possible, we simply used those localities as the basis for assigning individuals to “populations.” With some clustering of localities by geographic region if samples were few in number, we could define 11 populations on this basis (each represented by a pie chart in Fig. 1). There are no clear criteria for a priori grouping of these populations for a hierarchical analysis such as AMOVA (Excoffier et al. 1992).

Some liver cancers are not even typical HCC, but are composed primarily of small spindled cells, are difficult to characterize as epithelial by conventional immunohistochemical markers for

HCC, and best labeled simply as “primary liver cancer”, and their outcome may be considered similar to that of other undifferentiated primary carcinomas. We now recognize liver carcinomas can also be characterized as having arisen from the Hering canal (progenitor) cells (so-called cholangiolocarcinoma). These tumors Wnt inhibitor have a striking histologic appearance of altered cord-like and antler-shaped structures within a dense stromal background, often reminiscent www.selleckchem.com/screening/kinase-inhibitor-library.html of an aberrant ductal plate, and differ in many ways from conventional cholangiocarcinoma. If these tumors

and their stromal components are never carefully documented histologically, results of the sophisticated molecular -omics, micro-RNA studies will continue to be heterogenous, unfocused, and essentially irreproducible. We are, we fear, losing a valuable opportunity to correlate genotypic information with histopathologic phenotype of the plethora of cancers in these studies. In most published manuscripts on molecular signatures of HCC, the cancer phenotype presented is limited to size and number of lesions, presence of microvascular invasion, serum alpha-fetoprotein levels, and, of course, Florfenicol disease recurrence or survival. Detailed histopathology is commonly missing from such articles and, yet, has much to offer. An example of this lack of attention to details of histopathology at the recent ILCA meeting was the luncheon workshop for Molecular Markers of HCC. Both moderators made

a point of stating early on in the meeting that “liver biopsies need to be done on all liver cancer”. Why, they asked? They went on to answer: To be able to study predictors (molecular), as well as prognosis (molecular). Also noted, however, in the seminar was the diversity of (molecular) platforms for these highly sophisticated studies, the plethora of genetic, inflammatory, metabolic pathways and data being generated, and our current need, therefore, for highly sophisticated, costly, and center-specific techniques for analysis of large numbers of cases and datasets. Yet, no discussion whatsoever occurred of the possible presence or significance of correlations or differentiating histopathologic subtypes. It seems unfortunate that the history of our discipline in hepatology is rapidly being lost to the memories of the young generation.

A series of studies that directly addressed the molecular mechanisms that control liver development and hepatic excretory function served as the biologic basis for enhanced understanding of the molecular basis of hepatobiliary dysfunction manifest as intrahepatic Vismodegib chemical structure cholestasis.[27, 28, 75] The heterogeneity reflected inherited defects in mechanisms involved in the generation of bile flow, specifically canalicular transport proteins resulting in substrate retention manifest

as cholestasis. Patients with the most common types of PFIC were shown to harbor mutations in genes encoding proteins involved in bile acid transport: (1) ATP8B1 gene, encoding FIC1 (patients with PFIC Type 1); (2) ABCB11 gene, encoding the bile salt export

pump (BSEP, patients with PFIC Type 2); and (3) ABCB4 gene, encoding the multidrug Stem Cell Compound Library screening resistance protein-3 (MDR3, patients with PFIC Type 3). In addition, the complex phenotype, molecular genetics, and inheritance pattern of Alagille syndrome were defined, with linkage to mutations in human Jagged1 (JAG1), which encodes a ligand for the Notch receptor.[76-78] The Notch gene family encodes evolutionarily conserved transmembrane receptors involved in cell fate specification during embryonic development. This locus controls the ability of cells that are nonterminally differentiated to respond to differentiation and proliferation signals. In Alagille syndrome, mutations in JAG1 disrupt the gene product, altering cell-to-cell signaling during development. These investigations allowed classification of these disorders into distinct subsets[28] (Table 1). To translate this knowledge into practical applications in the clinic, Jorge Bezerra and co-workers[79] developed the “Jaundice Chip,”

which uses a “resequencing” platform that enables the detection of mutations of these genes. Studies also addressed the importance of heterozygosity Leukotriene-A4 hydrolase for these genes in creating genetic susceptibility to injury initiated by other agents such as drugs, toxins, or viruses. In addition, detailed understanding of the underlying pathophysiology of altered bile acid transport allowed for the development of specific targeted therapy. Based on initial studies, ursodeoxycholic acid became popular as a therapeutic agent in patients with intrahepatic cholestasis; this is now an accepted form of therapy worldwide.[80, 81] The body of knowledge related to hepatobiliary disease in children expanded in other needed areas. Enigmatic disorders presenting as acute liver failure, chronic hepatitis, or hepatocellular carcinoma yielded to biochemical analysis and molecular dissection and were proven to be caused by inborn errors of lipid, amino acid, or carbohydrate metabolism. The recognition of the metabolic basis for liver disease allowed for targeted nontransplant strategies for the management of affected patients.

) Pathology encountered Polypectomy (No.) CIT TPT 66M Acute angulation Colonoscopy (2) Diverticulosis Yes (1) <5 min 16 min 71F Bowel tortuosity Colonoscopy, Single balloon colonoscopy nil Yes (2) <10 min 23 min 79F Bowel tortuosity Colonoscopy nil Yes (1) <5 min 20 min 70M Bowel tortuosity, acute angulation Colonoscopy (3) Diverticulosis Yes (2) <10 min selleck kinase inhibitor 33 min Conclusions: Performance of colonoscopy using both the distal cap attachment and water insufflation appeared to facilitate caecal intubation

in patients in whom previous colonoscopies have been unsuccessful due to technical difficulties. Water insufflation in the left colon may straighten the left colon and shorten caecal intubation time. A randomized study is ongoing to confirm these findings. T HAMPE,1 JS FREIMAN1 1Department of Gastroenterology and Hepatology, St George Hospital, Kogarah, NSW Background: For an explosion to occur, a combustible gas together with a limiting concentration of oxygen and an ignition source need to coincide (1,2). An explosion can NVP-BGJ398 solubility dmso occur over a defined range of concentration for a combustible gas defined by its lower and upper explosion levels. Such explosions are rare but well documented in the colon and insufflation with CO2 may prevent them. Aims: 1 To report the

first ever case study of a gastric explosion induced by APC during gastroscopy. 2 To recommend a simple change in clinical practice to prevent this rare complication. Case Study: A 70-year-old male presented to our hospital with melena for 2 weeks. Adenocarcinoma of the gastric antrum was recently diagnosed and staged by abdominal CT as T3N1M0. On admission, he was pale but hemodynamically stable. FBC showed a microcytic anemia, with a hemoglobin of 91 g/dl. Gastroscopy was performed using air insufflation. A moderate amount of altered blood was seen throughout the stomach but there was no obvious food residue. A 5 cm malignant ulcer in the antrum was seen to partially obstruct the pylorus, and there was diffuse oozing of blood GBA3 from the ulcer

rim. In an attempt to induce hemostasis, APC was applied using the ERBVIO 200d unit (ERBE Elektromedizin GmbH, Germany). Coinciding with the ignition, an instant explosion was felt and heard by all endoscopy staff present in theater. There was immediate collapse of the gastric lumen with loss of vision. With reinsufflation, small bowel loops were seen and a diagnosis was made of an APC-induced gastric explosion with perforation of the stomach. The patient was transferred to an adjacent operating theatre, where he underwent an immediate laparotomy. The stomach was perforated with long lacerations both on the greater and lesser curvatures, extending from the antrum proximal to the cancer to the distal fundus. A palliative subtotal gastrectomy was performed to prevent both ongoing bleeding and impending gastric outlet obstruction.

As shown in Fig. 1A, β2SP overexpression decreased the expression of several proteins responsible for cell cycle regulation including phosphorylated Rb (pRb). Comparing protein expression from identical preparations,

the most dramatic reduction in expression was for CDK4 (33% of control), suggesting that CDK4 is a downstream effector in cell cycle regulation mediated by β2SP signaling. Then we further compared the expression levels of CDK4, cyclin D1, pRb, and Rb upon transfection of β2SP in HepG2 and SNU475 cells in three independent experiments. The most remarkable reductions of CDK4 were shown in HepG2 (39%) and SNU475 (31%) cells (Fig. 1B). However, it was not clear that the change in CDK4 due to the loss of β2SP was sufficient to disrupt the cell cycle. Thus, we tested whether the increase in Rb phosphorylation Tamoxifen was due to the down-regulation of β2SP or activation of CDK4. We inhibited β2SP expression in SNU-475 cells by the infection of a lentivirus containing shRNA against β2SP and then analyzed Rb phosphorylation. β2SP expression was decreased by 44% after lentiviral infection and Rb phosphorylation

was increased by 55%, whereas selleck screening library the levels of Rb were unchanged (Fig. 1C). To determine whether CDK4 is responsible for Rb phosphorylation due to the down-regulation of β2SP, we inhibited CDK4 expression by siRNA in SNU-475 cells infected with β2SP shRNA. CDK4 siRNA in the presence of β2SP shRNA restored Rb phosphorylation to basal levels (Fig. 1C). These results suggest that CDK4 is a key regulator of Rb phosphorylation affected by β2SP expression. We then determined whether the induction of CDK4 expression due to the down-regulation of β2SP accelerates cell cycle progression. SNU-475

cells were infected with the β2SP shRNA lentivirus followed by treatment with a CDK4 inhibitor, and then analyzed cell cycle phases by fluorescence-activated cell sorting (FACS) with propidium iodide (PI) staining. The number of cells in G1 phase was significantly decreased from 46% to 35% upon the knockdown of β2SP (Fig. 2A,B). Additional treatment with CDK inhibitor (200 nM) in β2SP short hairpin RNA (shRNA)-treated cells returned 43% of the cells to ADP ribosylation factor G1. However, we did not detect the additional accumulation of cells in G1 phase in control lentiviral-treated cells exposed to the same CDK4 inhibitor. Taken together, these data demonstrate that dysregulation of the cell cycle resulting from the disruption of β2SP expression is mediated by CDK4 activation and Rb phosphorylation. We further investigated the mechanism by which β2SP modulates CDK4 by examining interactions between these proteins. Recent reports indicate that CDK4 phosphorylates Smad3 to inhibit its transcriptional activity and antiproliferative functions.7 Thus, we sought to determine whether CDK4 phosphorylates β2SP as it does Smad3.

As shown in Fig. 1A, β2SP overexpression decreased the expression of several proteins responsible for cell cycle regulation including phosphorylated Rb (pRb). Comparing protein expression from identical preparations,

the most dramatic reduction in expression was for CDK4 (33% of control), suggesting that CDK4 is a downstream effector in cell cycle regulation mediated by β2SP signaling. Then we further compared the expression levels of CDK4, cyclin D1, pRb, and Rb upon transfection of β2SP in HepG2 and SNU475 cells in three independent experiments. The most remarkable reductions of CDK4 were shown in HepG2 (39%) and SNU475 (31%) cells (Fig. 1B). However, it was not clear that the change in CDK4 due to the loss of β2SP was sufficient to disrupt the cell cycle. Thus, we tested whether the increase in Rb phosphorylation Rapamycin in vitro was due to the down-regulation of β2SP or activation of CDK4. We inhibited β2SP expression in SNU-475 cells by the infection of a lentivirus containing shRNA against β2SP and then analyzed Rb phosphorylation. β2SP expression was decreased by 44% after lentiviral infection and Rb phosphorylation

was increased by 55%, whereas Poziotinib in vitro the levels of Rb were unchanged (Fig. 1C). To determine whether CDK4 is responsible for Rb phosphorylation due to the down-regulation of β2SP, we inhibited CDK4 expression by siRNA in SNU-475 cells infected with β2SP shRNA. CDK4 siRNA in the presence of β2SP shRNA restored Rb phosphorylation to basal levels (Fig. 1C). These results suggest that CDK4 is a key regulator of Rb phosphorylation affected by β2SP expression. We then determined whether the induction of CDK4 expression due to the down-regulation of β2SP accelerates cell cycle progression. SNU-475

cells were infected with the β2SP shRNA lentivirus followed by treatment with a CDK4 inhibitor, and then analyzed cell cycle phases by fluorescence-activated cell sorting (FACS) with propidium iodide (PI) staining. The number of cells in G1 phase was significantly decreased from 46% to 35% upon the knockdown of β2SP (Fig. 2A,B). Additional treatment with CDK inhibitor (200 nM) in β2SP short hairpin RNA (shRNA)-treated cells returned 43% of the cells to Branched chain aminotransferase G1. However, we did not detect the additional accumulation of cells in G1 phase in control lentiviral-treated cells exposed to the same CDK4 inhibitor. Taken together, these data demonstrate that dysregulation of the cell cycle resulting from the disruption of β2SP expression is mediated by CDK4 activation and Rb phosphorylation. We further investigated the mechanism by which β2SP modulates CDK4 by examining interactions between these proteins. Recent reports indicate that CDK4 phosphorylates Smad3 to inhibit its transcriptional activity and antiproliferative functions.7 Thus, we sought to determine whether CDK4 phosphorylates β2SP as it does Smad3.

The protective effect of HLA-B27 and the strong immune pressure mediated by the immunodominant HLA-B27 epitope have been identified in HCV genotype 1 infection only. Although HCV genotype 1 is the most prevalent genotype in North America (subtype 1a > 1b) and Europe (subtype

1b > 1a), other genotypes may become more relevant in the near future, because they predominate in Wnt inhibitor many developing countries with a high incidence of HCV infection as well as in defined cohorts such as injection drug users, where HCV genotype 3a frequency is increasing.22 Intriguingly, the immunodominant HLA-B27 NS5B2841-2849 epitope region is highly conserved within but not between different HCV genotypes. Based on our previous findings in patients infected with HCV genotype 1,6 we therefore

hypothesized that this epitope region may not be targeted by HCV-specific CD8+ T cells in patients infected with HCV genotypes other than genotype 1, abrogating the protective effect of HLA-B27 in these patients. This was addressed in the current study by analyzing a new cohort of patients with acute or chronic HCV genotype 3a infection. Indeed, we could demonstrate that CD8+ T cells specific for the HCV genotype 1 NS5B2841-2849 epitope (ARMILMTHF) RAD001 cost do not recognize the HCV genotype 3a peptide (V RM VM MTHF). In addition, patients with genotype 3a infection do not target the region corresponding to the B27-epitope. Accordingly, there is no evidence of mutational escape in genotype 3 isolates supporting lack of HLA-B27-associated T-cell pressure

on this region in genotype 3a-infected patients. Collectively, these data suggest that HCV genotype 3a lacks the HLA-B27 epitope, which is immunodominant in HCV genotype 1 infection and most likely significantly contributes to the protective effect of HLA-B27. It Thymidylate synthase is not clear why patients infected with genotype 3a are unable to target the genotype 3a epitope region, especially because the main HLA-B27 binding anchors (arginine at position 2 and phenylalanine at the C-terminus) are conserved between the genotypes. The variant sequence might have an impact on binding to HLA-B27 despite intact primary anchor residues. Alternatively, it has been proposed previously that the failure of the immune system to target certain epitope variants that are efficiently presented by the restricting HLA allele is caused by a hole in the T-cell repertoire.23 In this context, it is intriguing to note that both the variant described in the previous study as well as the genotype 3a epitope variant described here contain a leucine to methionine (L M) substitution at amino acid residue four. We also compared the frequency of HLA-B27 positivity in patients chronically infected with genotypes 1 and 3a, respectively.

The current report by the Wells laboratory in HEPATOLOGY17 provides the strongest evidence against EMT in the liver as a source of myofibroblasts. This study uses lineage tracing generated by crossing the alpha-fetoprotein (AFP) cre mouse with the ROSA26YFP stop mouse to trace the fate of any cell ever expressing AFP (Fig. 1A). As expected, all the cholangiocytes and all the hepatocytes were genetically

labeled, because they are derived from AFP-expressing precursor cells. Furthermore, AFP+ progenitor cells were also irreversibly genetically marked. The critical result was that after inducing liver fibrosis by a variety of methods, none of the resulting myofibroblasts originated from the genetically marked epithelial (AFP+) cells. This important article corroborates and extends two previous studies in assessing the selleck inhibitor contribution of epithelial cells to myofibroblasts in liver fibrosis. The first article used the robust albumin cre mouse to mark all the hepatocytes.16 Pexidartinib price The second study used a recently developed inducible cytokeratin-19 cre mouse to

mark cholangiocytes.18 Both studies failed to detect any myofibroblasts in the fibrotic liver that originated from the epithelial cells. Thus, using three independent strains of cre mice as well as independent experimental methods (fluorescence-activated cell sorting, immunofluorescence to detect myofibroblast markers, and β-galactosidase enzymatic activity), these combined studies demonstrate that hepatic epithelial cells do not contribute to experimental liver fibrosis (Fig. 1B). So what are the caveats? The most obvious is that that these powerful techniques should be applied to assess EMT in additional experimental models in which there is severe injury to epithelial cells, such as in alcoholic liver disease. Furthermore, Epothilone B (EPO906, Patupilone) the short length of experimental liver fibrosis (3 weeks to 3 months) may not reflect the cellular pathophysiology

that occurs in chronic human liver disease, including the reactive ductile proliferation seen in patients. Therefore, the coexpression of epithelial and mesenchymal markers in cells from biopsies from patients with primary biliary cirrhosis or primary sclerosing cholangitis requires careful analysis and follow-up. Finally, studies consistently demonstrate that injured epithelial cells change their gene expression to produce fibrogenic agonists. Injured hepatocytes produce hedgehog ligands that activate stellate cells,19 and injured cholangiocytes produce the fibrogenic cytokine TGFβ.20 Thus, although there is no current evidence that myofibroblasts originate from hepatic epithelial cells, the original concept of type 2 EMT as injury-induced changes in epithelial cells continues to provide insight into liver fibrosis. “
“We read with interest the recent article by Sangro et al.

In particular, IL-6 has been put forward as the molecular

component released by non-stem cancer cells to allow their conversion to cancer stem cells, and thereby maintain a dynamic equilibrium between these two tumor intrinsic cell types.82 Stat3 upregulates proteins of the Bcl-2 pro-survival family. In epithelial cells, it also induces other proteins that indirectly suppress apoptosis, such as the chaperone protein Hsp70, the C-type lectin-type RegIIIβ, and survivin,83 which are all overexpressed in CRC and IBD. The latter proteins not only suppress apoptosis, but might also promote cell cycle progression through binding to Cdc2. Stat3 also promotes the G1/S phase transition of the cell cycle more directly through the transcriptional selleck compound induction of cyclinB1, cdc2, c-myc, and cyclinD1, Bortezomib order and repression of the cell cycle inhibitor p21.83 As a third tumor-intrinsic property, Stat3 induces expression of the angiogenic factors, VEGF and HIF1α.83 Thus, excessive activation of Stat3 correlates with tumor invasion and metastasis in a variety of cancers. In the absence of epithelial Stat3 expression, the CAC model yields reduced tumor formation. Conversely, excessive Stat3 activation, through epithelial-specific Socs3 ablation or introduction of the Socs3-binding deficient gp130Y757F mutation, results in increased multiplicity and size of these tubular adenomas.84,85 Administration of

hyper-IL-6 (a fusion protein between IL-6 and soluble IL-6Rα), but not of Phosphoprotein phosphatase IL-6, also increased tumor burden in CAC-challenged mice,85 suggesting that the extent of membrane-bound IL-6Rα, rather than gp130, limit the tumor-promoting

response. Consistent with these observations, we found functional redundancy between IL-6 and IL-11, and that both cytokines conferred Stat3-dependent, epithelial resistance to apoptosis and colitis.84 Genetic deficiency for the ligand binding IL-11Rα subunit in the CAC model significantly abrogates colonic tumor formation in gp130Y757F mice, while systemic reduction of Stat3 expression in gp130Y757FStat3+/− mice also reduced their susceptibility to colon tumorigenesis in the CAC model (Ernst et al., unpubl. observ., 2011). Furthermore, intestinal tumor burden is reduced in ApcMin mice lacking IL-6, and in ApcMin mice that are also haplo-insufficient for IL-11Rα or Stat3. However, IL-11 administration protected against radiation-induced mucositis, suggesting that IL-11 signaling might play a physiological role in the maintenance of intestinal epithelial integrity. Notwithstanding the central role played by excessive epithelial Stat3 signaling for the promotion of intestinal tumorigenesis, it has been recently suggested that this might also be part of an epigenetic switch mechanism that initiates tumor formation from non-transformed cells, rather than solely-expanding neoplastic cells that have arisen after exposure to mutagens.

The stratification of cell grading in early HCC nodules investigated before any treatment differs substantially from that reported in surgical specimens, where the HCC nodules were greater in size and more dedifferentiated (42%-60% grade II and III versus 28%-46% grade IV).14, 18-22 Although a correlation has been demonstrated between cell grading and volume of the tumor in surgical studies,11 such a correlation was not apparent in our study, which only included HCCs <3 cm. Indeed, the median volume of tumors we investigated was the same

across all the grading categories (no patient with grade IV tumors), each volumetric set of HCC (<1 cm, 1-2 cm, >2 cm) containing more grade II and III than grade I tumors. selleck kinase inhibitor Although we acknowledge that medium to poorly Deforolimus molecular weight differentiated HCC nodules can be more confidently diagnosed by FNB than well-differentiated tumors, our approach of comparing intranodular and extranodular tissue and the yield of liver cores of adequate length as those obtained with a trenchant needle, should have reasonably attenuated the risk of underestimation of tumor grade in our study. The lack of concordance we demonstrated in 28% of paired

FNB examinations should not have subverted our correlation analysis in small tumors, because only one of the five discordant nodules was grade I versus grade II, whereas the remaining four nodules were discordant for grade II and III, to give a clinically meaningful discordance between paired FNB examinations of 5% only. A previous study from our group comparing the accuracy of dynamic contrast imaging techniques and FNB to diagnose HCC in cirrhosis allowed us to assess whether tumor cell grading had any influence on the accuracy of dynamic Tideglusib contrast imaging techniques that are endorsed for the noninvasive diagnosis of HCC.9 To maximize the diagnostic accuracy of FNB, we used a 21-gauge trenchant needle for microhistology, resulting in tissue cores of 1.6 cm, on average. Moreover, by sampling all patients for both nodular and extranodular liver parenchyma, the differential diagnosis between low-grade tumors

and dysplastic macroregenerative nodules was eased.23 Finally, to evaluate the sensitivity of the study, a set of patients underwent two intranodule biopsies, and the biopsy specimens were blindly examined by two pathologists who were unaware of the clinical findings. In our study, the diagnostic accuracy of dynamic contrast imaging techniques appeared to be attenuated in well-differentiated tumors compared with less differentiated tumors. This may have clinical implications, because the current standard of care for the radiological diagnosis of HCC, represented by the combination of CE-US and MRI, has been shown to have a sensitivity of 33.3% and a specificity of 100% in the setting of 0.5- to 2-cm tumors occurring in patients with cirrhosis.