During the 1990s, the overall incidence of SOS among patients at our http://www.selleckchem.com/products/VX-809.html center was 38% (7% severe) following CY/TBI and 12% (2% severe) following targeted oral busulfan plus CY.20, 22 However, the frequency and severity of SOS have fallen dramatically recently because: (1) doses of TBI >14 Gy are seldom used; (2) fludarabine is replacing CY; (3) patients at risk for SOS are being given conditioning regimens that do not contain either CY or TBI >12 Gy; (4) the incidence of chronic hepatitis C is low; and (5) therapeutic drug

monitoring allows personalized dosing of chemotherapy drugs that have variable metabolism. Pediatric patients receiving busulfan/melphalan conditioning regimens remain at risk. A meta analysis suggests that prophylaxis with ursodiol prevents SOS, but the largest randomized trial of ursodiol that specifically tracked SOS as an endpoint found no evidence of protection.2 It seems likely find more that many past patients diagnosed as having SOS on the basis of jaundice had mostly cholestatic and not sinusoidal liver injury. The onset of SOS is heralded by an increase in liver size, right upper quadrant tenderness, renal sodium retention, and weight gain, occurring 10-20 days after the start of CY-based cytoreductive therapy and later after other myeloablative regimens. Hyperbilirubinemia follows these signs of portal hypertension by 4-10 days. Portal hypertension,

renal and lung dysfunction, and refractory thrombocytopenia strongly suggest SOS. Measurement of total serum bilirubin is a sensitive test for SOS this website but not a specific one. Elevations of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) weeks after the clinical onset of SOS reflect ischemic hepatocyte necrosis from sinusoidal fibrosis (Fig. 1D).23 Several plasma proteins have been reported to be abnormally high in patients with SOS (endothelial cell markers, thrombopoietin, proinflammatory

cytokines, vascular endothelial growth factor, and procollagen peptides); some laboratory tests are abnormally low in patients with SOS (protein C, antithrombin III, and platelet counts) (reviewed in Deleve17). It is not clear whether any laboratory tests have diagnostic or prognostic utility beyond the clinical criteria of weight gain, jaundice, and hepatomegaly. Imaging studies of the liver are useful for demonstrating hepatomegaly, ascites, periportal edema, attenuated hepatic venous flow, and gallbladder wall edema consistent with SOS,24 as well as excluding other causes of hepatomegaly and jaundice. Abnormal findings later in the course of SOS may include an enlarged portal vein diameter, slow or reversed flow in the portal vein or its segmental branches, high congestion index, portal vein thrombosis, and increased resistive index to hepatic artery flow. Unfortunately, ultrasound findings very early in the course of SOS-when there is diagnostic uncertainty-do not appear to add to the information provided by clinical criteria.

During the 1990s, the overall incidence of SOS among patients at our BVD-523 purchase center was 38% (7% severe) following CY/TBI and 12% (2% severe) following targeted oral busulfan plus CY.20, 22 However, the frequency and severity of SOS have fallen dramatically recently because: (1) doses of TBI >14 Gy are seldom used; (2) fludarabine is replacing CY; (3) patients at risk for SOS are being given conditioning regimens that do not contain either CY or TBI >12 Gy; (4) the incidence of chronic hepatitis C is low; and (5) therapeutic drug

monitoring allows personalized dosing of chemotherapy drugs that have variable metabolism. Pediatric patients receiving busulfan/melphalan conditioning regimens remain at risk. A meta analysis suggests that prophylaxis with ursodiol prevents SOS, but the largest randomized trial of ursodiol that specifically tracked SOS as an endpoint found no evidence of protection.2 It seems likely buy Sorafenib that many past patients diagnosed as having SOS on the basis of jaundice had mostly cholestatic and not sinusoidal liver injury. The onset of SOS is heralded by an increase in liver size, right upper quadrant tenderness, renal sodium retention, and weight gain, occurring 10-20 days after the start of CY-based cytoreductive therapy and later after other myeloablative regimens. Hyperbilirubinemia follows these signs of portal hypertension by 4-10 days. Portal hypertension,

renal and lung dysfunction, and refractory thrombocytopenia strongly suggest SOS. Measurement of total serum bilirubin is a sensitive test for SOS learn more but not a specific one. Elevations of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) weeks after the clinical onset of SOS reflect ischemic hepatocyte necrosis from sinusoidal fibrosis (Fig. 1D).23 Several plasma proteins have been reported to be abnormally high in patients with SOS (endothelial cell markers, thrombopoietin, proinflammatory

cytokines, vascular endothelial growth factor, and procollagen peptides); some laboratory tests are abnormally low in patients with SOS (protein C, antithrombin III, and platelet counts) (reviewed in Deleve17). It is not clear whether any laboratory tests have diagnostic or prognostic utility beyond the clinical criteria of weight gain, jaundice, and hepatomegaly. Imaging studies of the liver are useful for demonstrating hepatomegaly, ascites, periportal edema, attenuated hepatic venous flow, and gallbladder wall edema consistent with SOS,24 as well as excluding other causes of hepatomegaly and jaundice. Abnormal findings later in the course of SOS may include an enlarged portal vein diameter, slow or reversed flow in the portal vein or its segmental branches, high congestion index, portal vein thrombosis, and increased resistive index to hepatic artery flow. Unfortunately, ultrasound findings very early in the course of SOS-when there is diagnostic uncertainty-do not appear to add to the information provided by clinical criteria.

During the 1990s, the overall incidence of SOS among patients at our Protein Tyrosine Kinase inhibitor center was 38% (7% severe) following CY/TBI and 12% (2% severe) following targeted oral busulfan plus CY.20, 22 However, the frequency and severity of SOS have fallen dramatically recently because: (1) doses of TBI >14 Gy are seldom used; (2) fludarabine is replacing CY; (3) patients at risk for SOS are being given conditioning regimens that do not contain either CY or TBI >12 Gy; (4) the incidence of chronic hepatitis C is low; and (5) therapeutic drug

monitoring allows personalized dosing of chemotherapy drugs that have variable metabolism. Pediatric patients receiving busulfan/melphalan conditioning regimens remain at risk. A meta analysis suggests that prophylaxis with ursodiol prevents SOS, but the largest randomized trial of ursodiol that specifically tracked SOS as an endpoint found no evidence of protection.2 It seems likely Gefitinib supplier that many past patients diagnosed as having SOS on the basis of jaundice had mostly cholestatic and not sinusoidal liver injury. The onset of SOS is heralded by an increase in liver size, right upper quadrant tenderness, renal sodium retention, and weight gain, occurring 10-20 days after the start of CY-based cytoreductive therapy and later after other myeloablative regimens. Hyperbilirubinemia follows these signs of portal hypertension by 4-10 days. Portal hypertension,

renal and lung dysfunction, and refractory thrombocytopenia strongly suggest SOS. Measurement of total serum bilirubin is a sensitive test for SOS check details but not a specific one. Elevations of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) weeks after the clinical onset of SOS reflect ischemic hepatocyte necrosis from sinusoidal fibrosis (Fig. 1D).23 Several plasma proteins have been reported to be abnormally high in patients with SOS (endothelial cell markers, thrombopoietin, proinflammatory

cytokines, vascular endothelial growth factor, and procollagen peptides); some laboratory tests are abnormally low in patients with SOS (protein C, antithrombin III, and platelet counts) (reviewed in Deleve17). It is not clear whether any laboratory tests have diagnostic or prognostic utility beyond the clinical criteria of weight gain, jaundice, and hepatomegaly. Imaging studies of the liver are useful for demonstrating hepatomegaly, ascites, periportal edema, attenuated hepatic venous flow, and gallbladder wall edema consistent with SOS,24 as well as excluding other causes of hepatomegaly and jaundice. Abnormal findings later in the course of SOS may include an enlarged portal vein diameter, slow or reversed flow in the portal vein or its segmental branches, high congestion index, portal vein thrombosis, and increased resistive index to hepatic artery flow. Unfortunately, ultrasound findings very early in the course of SOS-when there is diagnostic uncertainty-do not appear to add to the information provided by clinical criteria.

1A). This was supported by the observation at E17.5 that all cells on the parenchymal side of the biliary structures expressed TβRII (arrowheads), whereas cells on the portal

side no longer expressed INCB024360 concentration TβRII (open arrowheads, Supporting Fig. 1). At postnatal day 7, biliary cells had differentiated in Hnf6−/− and in Hnf1bloxP/loxP-Alfp-Cre livers because they were SOX9+/HNF4− (arrows, Supporting Fig. 2A). Therefore, embryonic biliary differentiation defects seemed to resolve, but this was not sufficient to allow normal tubulogenesis: Hnf6−/− livers showed DPM, and HNF1β-deficient livers showed heterogeneity, combining DPM and dysplastic ducts (Supporting Fig. 2A,B) within the same liver. Therefore, in HNF1β-deficient mice, a homogeneous embryonic phenotype gives rise to a heterogeneous postnatal phenotype. We concluded that the absence of HNF6 induces an early defect in biliary cell differentiation, whereas the

lack of HNF1β leads to deficient maturation of PDS; both defects ultimately give rise to DPMs. There are no HNF6 mutations reported in humans. In contrast, patients with HNF1B (TCF2) mutations present with renal cysts and ABT-199 supplier diabetes syndrome (Mendelian Inheritance in Man #137920). There is phenotypic variability and in rare cases this syndrome is associated with bile duct paucity.24, 25 We therefore looked for the presence of DPMs in a patient with HNF1B mutation. This patient had multicystic kidneys and died at 4 days from pulmonary insufficiency; analysis of the HNF1B gene revealed heterozygous deletion of exon 6. Immunostaining of sections showed DPMs constituted of clusters of SOX9+/Ecad+ cells (arrows) and short cords of HNF4−/Ecad+ see more cells (arrowheads) in the portal mesenchyme (Fig.

1B). Dysplastic ducts were also found (Supporting Fig. 3). Therefore, HNF1B mutation in humans can be associated not only with bile duct paucity but also with DPMs and duct dysplasia. The limited availability of samples from patients with HNF1B mutations precludes analysis of the morphogenesis of DPMs. Therefore, we speculated that DPMs develop similarly in patients and in Hnf1bloxP/loxP-Alfp-Cre mice. This was supported by our observations that bile duct development in humans proceeds by transient asymmetry, like in mice (Fig. 1C). Indeed, the liver of a normal fetus at the 11th week of gestation (W) showed PDS with asymmetrical expression of SOX9. Because maturation of ducts is not equal throughout the liver, ducts entirely lined by SOX9+ cells were also found within the same liver. HNF6 controls the formation of primary cilia in the pancreas and HNF1β regulates genes involved in cilium function in mouse kidneys.8, 15 Therefore, we investigated how ciliogenesis proceeds in the biliary tract of Hnf6−/− and Hnf1bloxP/loxP-Alfp-Cre mice. Primary cilia were identified as acetylated tubulin-stained dots in wild-type livers at E17.5 (Fig. 2). In contrast, little or no cilia were detected on HNF6- and HNF1β-deficient biliary cells.

Therefore, the main value of these tests is to exclude advanced fibrosis as screening tests.

Based on our data, it is reasonable to consider liver learn more biopsy in patients whose LSM is 7.9 kPa or above. When transient elastography is not available, the biochemical tests reported in this study are reasonable screening tests despite a lower overall accuracy. LSM has been shown to be spuriously increased in patients with acute hepatitis and extrahepatic cholestasis, indicating that the stiffness of the liver is not attributable to fibrosis alone.26–29 One unique feature of NAFLD patients is the accumulation of subcutaneous, prehepatic, and hepatic fat. Whether this would affect LSM has major clinical implications. In patients with chronic hepatitis C, hepatic steatosis does not appear to influence LSM, although patients with severe steatosis were underrepresented.26

In this study, we clearly showed that hepatic steatosis did not increase LSM in NAFLD subjects. Although subcutaneous and prehepatic fat thickness was not measured, patients with high BMI also did not have increased LSM after adjusting for fibrosis stage. Moreover, ALT level and the NAFLD activity score did not influence LSM. This is likely because severe buy Ipatasertib necroinflammation is rare in NAFLD subjects, and a milder degree of necroinflammation has no major impact on LSM. Besides, ALT selleckchem level in NAFLD subjects mainly reflects the degree of hepatic steatosis and correlates poorly with necroinflammation.30

In patients with chronic hepatitis C, discordance between transient elastography and histology occurs more commonly if the IQR/LSM ratio is high.31 In our study, discordance occurred mainly in patients with shorter liver biopsy lengths and lower fibrosis stages. Both factors indicate that the discordance was attributable to understaging by histology as a result of sampling bias. One possible explanation of the phenomenon is that the distribution of fibrous tissue may be less even in NAFLD patients. In a study of 41 subjects undergoing right-lobe and left-lobe liver biopsies during bariatric surgery, the kappa coefficient for fibrosis staging was only 0.53.7 Although we cannot recommend relying on transient elastography regardless of the IQR/LSM ratio because most of our patients had IQR/LSM ratio less than 0.3 at inclusion, our study serves as a reminder that when a noninvasive test disagrees with histological results, the latter may be inaccurate. By mathematical modeling, the AUROC of a noninvasive test is limited by the biopsy sensitivity and specificity even if the test has perfect accuracy.32 Our study has several limitations. First, liver biopsy was used as the gold standard, and liver biopsy specimens were assessed by two pathologists. Sampling bias could not be excluded.

Therefore, the main value of these tests is to exclude advanced fibrosis as screening tests.

Based on our data, it is reasonable to consider liver selleck screening library biopsy in patients whose LSM is 7.9 kPa or above. When transient elastography is not available, the biochemical tests reported in this study are reasonable screening tests despite a lower overall accuracy. LSM has been shown to be spuriously increased in patients with acute hepatitis and extrahepatic cholestasis, indicating that the stiffness of the liver is not attributable to fibrosis alone.26–29 One unique feature of NAFLD patients is the accumulation of subcutaneous, prehepatic, and hepatic fat. Whether this would affect LSM has major clinical implications. In patients with chronic hepatitis C, hepatic steatosis does not appear to influence LSM, although patients with severe steatosis were underrepresented.26

In this study, we clearly showed that hepatic steatosis did not increase LSM in NAFLD subjects. Although subcutaneous and prehepatic fat thickness was not measured, patients with high BMI also did not have increased LSM after adjusting for fibrosis stage. Moreover, ALT level and the NAFLD activity score did not influence LSM. This is likely because severe X-396 necroinflammation is rare in NAFLD subjects, and a milder degree of necroinflammation has no major impact on LSM. Besides, ALT selleck inhibitor level in NAFLD subjects mainly reflects the degree of hepatic steatosis and correlates poorly with necroinflammation.30

In patients with chronic hepatitis C, discordance between transient elastography and histology occurs more commonly if the IQR/LSM ratio is high.31 In our study, discordance occurred mainly in patients with shorter liver biopsy lengths and lower fibrosis stages. Both factors indicate that the discordance was attributable to understaging by histology as a result of sampling bias. One possible explanation of the phenomenon is that the distribution of fibrous tissue may be less even in NAFLD patients. In a study of 41 subjects undergoing right-lobe and left-lobe liver biopsies during bariatric surgery, the kappa coefficient for fibrosis staging was only 0.53.7 Although we cannot recommend relying on transient elastography regardless of the IQR/LSM ratio because most of our patients had IQR/LSM ratio less than 0.3 at inclusion, our study serves as a reminder that when a noninvasive test disagrees with histological results, the latter may be inaccurate. By mathematical modeling, the AUROC of a noninvasive test is limited by the biopsy sensitivity and specificity even if the test has perfect accuracy.32 Our study has several limitations. First, liver biopsy was used as the gold standard, and liver biopsy specimens were assessed by two pathologists. Sampling bias could not be excluded.

(HEPATOLOGY 2009.) Liver ischemia–reperfusion (I/R) injury is an unavoidable consequence of partial hepatectomy, liver transplantation, and hypovolemic shock and remains a significant clinical problem. In addition to hepatocyte necrosis and apoptosis, severe liver I/R injury can induce a dysregulated systemic inflammatory response that culminates in multiple organ failure.1, 2 The current treatment of liver I/R injury is merely supportive care, and thus new therapeutic

strategies are needed. Hepatic I/R generates a complex array of signals that are initially Talazoparib supplier confined to the liver milieu. The ensuing sequence of events is characterized by ischemia-induced cytolysis of hepatocytes and the generation of reactive oxygen species (ROS). Subsequently, secondary activation of the innate immune system occurs with up-regulation of inflammatory cytokines and chemokines that promote additional hepatocyte death. Inflammatory agents known to potentiate hepatic I/R injury have been well described and include tumor necrosis factor (TNF), interleukin (IL)-1β and IL-12.3–5 In particular, TNF induces adhesion molecule

and chemokine expression leading to rapid infiltration of neutrophils, which are among the principal effectors of liver I/R injury.6 Toll-like receptors (TLRs) are pattern-recognition receptors that recognize conserved pathogen-associated molecular patterns. Activation of innate immunity through TLR ligation occurs in microbial infection. However, it is now apparent that TLRs can also recognize endogenous ligands. Liver I/R injury is exacerbated check details by activation of TLR4 by high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein released from dying cells.7–9 Meanwhile, TLR2 does not appear

to play a role in liver I/R injury, because TLR2−/− mice have similar selleck screening library serum alanine aminotransferase (ALT) to wild-type (WT) mice.10 The role of other individual TLRs in liver I/R is unknown. TLR9 is an endosomal protein that recognizes bacterial CpG as well as self-DNA.11, 12 Because liver I/R results in hepatocyte death and potential DNA release, we hypothesized that TLR9 contributes to the associated immune response. Furthermore, because the TLR9-mediated responses of dendritic cells and macrophages to bacterial DNA in vitro have been shown to be augmented by HMGB1,13, 14 we sought to determine the relationship between TLR9 and HMGB1 in liver I/R. ALT, alanine aminotransferase; DAMP, danger-associated molecular pattern; HMGB1, high-mobility group box 1; iCpG, inhibitory CpG sequence; IL, interleukin; I/R, ischemia–reperfusion; LSEC, liver sinusoidal endothelial cell; MCP-1; monocyte chemoattractant protein-1; NPC, nonparenchymal cells; ODN, oligodeoxy-nucleotide; ROS, reactive oxygen species; SEM, standard error of the mean; TLR, Toll-like receptor; TNF, tumor necrosis factor; WT, wild-type. Eight-week-old to 16-week-old WT CD45.

1994), and have some long-term associations (Marten and Psarakos 1999). Similar to the bottlenose dolphins described above, geographic isolation of spinner dolphins can produce extreme differences in social structure between populations, where the fluidity of the fission-fusion dynamics is replaced with long-term group fidelity and social stability (Karczmarski et al. 2005). The general pattern of the socioecology of mammalian groups shows considerable behavioral flexibility,

indicating that social variability is a common response to environmental variability (see Karczmarski et al. 2005). It is known that the spotted dolphin is closely related to Tursiops aduncus Small molecule library in vivo ICG-001 in vivo (LeDuc et al. 1999). They live in a similar habitat (Herzing 1997) and share some social structure characteristics (Herzing and Brunnick 1997, Welsh and Herzing 2008) with that of coastal bottlenose dolphins. However detailed sex-specific associations and social structure have yet to be explored, including male associations. Behavioral evidence over many years of research shows cooperative (including monopolization of females) and agonistic interactions between males (Herzing and Johnson 1997), but until now quantitative analyses have not been conducted. Of particular interest is whether the males

of this species form long-term strong associations and if so, are they similar to alliances seen in bottlenose dolphins of Sarasota, Fl (T. truncatus, Wells et al. 1987) and the sympatric bottlenose dolphins in the Bahamas (T. truncatus, Rogers et al. 2004) or the more complex multi-level alliance structure of their closely related cousins in Shark Bay, Australia (T. aduncus, Connor et al. 1992). This community of Atlantic spotted dolphins has been observed by the Wild Dolphin Project (WDP) since 1985 (Herzing 1996, 1997). The purpose of this

study was to provide a detailed analysis of association patterns in relation selleck kinase inhibitor to factors such as cluster designation (one community made up of the Northern, Central, and Southern clusters; Elliser and Herzing 2012), sex, and age class bonds. This study offers a unique look at the social structure and sex-specific bonds in a species other than the well-studied bottlenose dolphin, providing insight into the behavioral flexibility and ecological variability of social structure in small delphinids. Little Bahama Bank (LBB) is 64 km from the east coast of Florida, and north of West End, Grand Bahama Island (Fig. 1). The study area spans 60 km north to south and 8 km east to west and encompasses 480 km2. The sandbank is shallow, between 6 m and 16 m deep, and is surrounded by deep water (steep drop off to over 500 m into the Gulf Stream). It has a primarily sandy bottom, scattered with areas of rock, reef, and patches of seagrass (Thalassia testudimum).

1994), and have some long-term associations (Marten and Psarakos 1999). Similar to the bottlenose dolphins described above, geographic isolation of spinner dolphins can produce extreme differences in social structure between populations, where the fluidity of the fission-fusion dynamics is replaced with long-term group fidelity and social stability (Karczmarski et al. 2005). The general pattern of the socioecology of mammalian groups shows considerable behavioral flexibility,

indicating that social variability is a common response to environmental variability (see Karczmarski et al. 2005). It is known that the spotted dolphin is closely related to Tursiops aduncus www.selleckchem.com/products/sch772984.html PLX4032 manufacturer (LeDuc et al. 1999). They live in a similar habitat (Herzing 1997) and share some social structure characteristics (Herzing and Brunnick 1997, Welsh and Herzing 2008) with that of coastal bottlenose dolphins. However detailed sex-specific associations and social structure have yet to be explored, including male associations. Behavioral evidence over many years of research shows cooperative (including monopolization of females) and agonistic interactions between males (Herzing and Johnson 1997), but until now quantitative analyses have not been conducted. Of particular interest is whether the males

of this species form long-term strong associations and if so, are they similar to alliances seen in bottlenose dolphins of Sarasota, Fl (T. truncatus, Wells et al. 1987) and the sympatric bottlenose dolphins in the Bahamas (T. truncatus, Rogers et al. 2004) or the more complex multi-level alliance structure of their closely related cousins in Shark Bay, Australia (T. aduncus, Connor et al. 1992). This community of Atlantic spotted dolphins has been observed by the Wild Dolphin Project (WDP) since 1985 (Herzing 1996, 1997). The purpose of this

study was to provide a detailed analysis of association patterns in relation learn more to factors such as cluster designation (one community made up of the Northern, Central, and Southern clusters; Elliser and Herzing 2012), sex, and age class bonds. This study offers a unique look at the social structure and sex-specific bonds in a species other than the well-studied bottlenose dolphin, providing insight into the behavioral flexibility and ecological variability of social structure in small delphinids. Little Bahama Bank (LBB) is 64 km from the east coast of Florida, and north of West End, Grand Bahama Island (Fig. 1). The study area spans 60 km north to south and 8 km east to west and encompasses 480 km2. The sandbank is shallow, between 6 m and 16 m deep, and is surrounded by deep water (steep drop off to over 500 m into the Gulf Stream). It has a primarily sandy bottom, scattered with areas of rock, reef, and patches of seagrass (Thalassia testudimum).

31 Of interest, our microarray analysis unveiled the altered expression of genes involved in Wnt/β-catenin signaling; down-regulation of the Wnt antagonist Sox17 (P = 0.009), up-regulation of a Wnt

downstream effector Cyclin D1 (P = 0.001), and Doxorubicin solubility dmso modestly increased expression of the Wnt receptor Fzd7 (P = 0.098). Wnt/β-catenin signaling is integrally associated with the regulation of stem cells and development of cancer32 and activated Wnt/β-catenin signaling promotes the proliferation and transformation of hepatic stem/progenitor cells.3 Together, these results imply that enforced expression of Bmi1 results in an enhancement of stemness features and the acquisition of malignant potential in normal hepatic stem/progenitor cells, at least in part, through the activation of Wnt signaling. However, further analysis would be necessary to elucidate the relationship between Bmi1 and Wnt signaling. Surprisingly but importantly, none of the 75 down-regulated genes following Bmi1-overexpression was included among the 305 up-regulated genes in neural progenitor cells after Bmi1 knockdown.27 Likewise, there existed no overlapping genes between the current expression profile and the 101 commonly regulated genes following

BMI1 knockdown between medulloblastoma and Ewing sarcoma cells.33, 34 In contrast, we detected several genes down-regulated following Bmi1-overexpression in hepatic stem/progenitor see more cells which are also regulated by Bmi1 in hematopoietic stem/progenitor cells (data this website not shown). These findings support the fact that PcG proteins function in a cell type-specific manner and the composition of PcG complexes is highly dynamic and differs in different cell-types and even at different gene loci.35 A comparison of the down-regulated genes with the ChIP-on-chip data for PcG complexes in ESCs revealed five genes that are regulated by PRC1 in ESCs as potential direct targets of Bmi1 in hepatic stem/progenitor cells (Fig. 6B). One of these genes, Sox17, is an endodermal marker gene and Sox17−/− mice die in the embryonic stage because

the endoderm fails to form properly.22 Therefore, its role in hepatic stem cells remained obscure. In the present study, self-renewal capacity of hepatic stem cells was inversely correlated with the Sox17 expression levels. Furthermore, cotransduction of Sox17 with Bmi1 repressed tumorigenic capacity of Bmi1 in NOD/SCID mice. These findings suggest that Sox17 acts as a tumor suppressor in a specific type of tumor originating from hepatic stem cells. The finding that it is transcriptionally silenced by DNA methylation in human colon cancer cells further supports its role as a tumor suppressor gene.36 On the other hand, Sox17-knockdown in Dlk+ cells alone did not promote tumor initiation in immunodeficient mice.