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Abstract

The Easiest, Cheapest, and Safest WinsPostoperative pancreatic fistulae are a common and troublesome consequence of pancreatic surgery. Most fistulae heal with conservative management, although a variety of therapeutic strategies such as endoscopic intervention, fibrin glues, proton pump inhibitors, and somatostatin analogs have been employed to facilitate healing.The study by Klek et al from the Jagiellonian University Medical in Poland represents a randomized, controlled trial that compares parenterally with enterally administered nutrition on the healing of grade B pancreatic fistulae. Grade B fistulae includes relatively well patients with persistently draining fistulae. Patients with grade C fistulae are clinically less stable and often require aggressive operative intervention for fluid collections and infection in addition to the problems presented by the fistulae. Likewise, grade A fistulae often heal spontaneously with such rapidity that an assessment of different therapies would be difficult. For the class of pancreatic fistulae addressed in this study, the relative efficacy of parenteral or enteral nutrition for fistula healing was unknown.The authors randomized a total of 78 patients to either enteral or parenteral nutrition. The patients were monitored and received an equal number of calories. The results showed a significant advantage for enteral feeding with respect to fistula closure rate, time to healing, and overall costs. The odds ratio for fistula closure within 30 days was 2.6 times higher for enteral versus parenteral feeding. The results indicate that enteral feeding is not only more effective, but also more cost effective and associated with fewer complications.Why enteral nutrition prevailed was not explored, but leading candidates include a number of gastrointestinal hormones and peptides whose release by enteroendocrine cells is stimulated by enteral and not parenteral feeding (Figure 1).See page 157.Diagnostic and Functional Implications of CD116 in Inflammatory Bowel DiseaseThe immune system is characterized by adaptive and innate immune responses. The adaptive response is represented by a customized humoral or cell-mediated immune response. In contrast, the innate immune response is nonspecific and includes protective responses by macrophages, granulocytes, and neutrophils. Recent evidence suggests that defects in the innate immune system may serve a significant role in inflammatory bowel disease (IBD). The use of granulocyte-macrophage colony–stimulating factor (GM-CSF) represents one therapeutic approach for IBD that is focused on stimulating the innate immune system. GM-CSF therapy, however, has been characterized by variable clinical outcomes.The study by Goldstein et al focuses on the GM-CSF receptor, CD116, as a potential biomarker for IBD and a role in disease pathogenesis. As a biomarker, quantitative polymerase chain reaction is employed to compare CD116 expression in purified granulocytes from 10 patients with IBD against 10 healthy controls. CD116 mRNA levels were 65% lower among IBD patients compared with controls. Examination of other cytokine receptors showed no difference from controls.The authors extended their study to 52 patients with IBD and an equivalent number of healthy controls by using flow cytometry to quantify CD116 expression on purified monocytes and granulocytes. CD116 mean fluorescent intensities for granulocytes and monocytes were significant lower in IBD patients versus controls (P < .0001). When receiver operating characteristic curves were used to set a minimum threshold, the sensitivity and specificity of CD116 to detect IBD was 90% and 91%, respectively, for granulocytes, and 81% and 94%, respectively, for monocytes. For IBD patients, 82% displayed low CD116 levels in both granulocytes and monocytes, 12% expressed low levels in either granulocytes or monocytes, and 6% had normal levels in both cell lineages. In contrast, 87% of normal healthy controls expressed normal CD116 levels in granulocytes and monocytes, 13% had low levels in either granulocytes or monocytes, and none exhibited low levels in both granulocytes and monocytes. Notable is that CD116 expression was not affected by disease activity or medical treatment. Although more extensive evaluation of other autoimmune and gastrointestinal pathologies is still needed, CD116 demonstrated potential diagnostic power for IBD. The observed heterogeneity in CD116 expression among IBD patients also raises questions of whether it can stratify candidates for GM-CSF therapy. Likewise, whether CD116 is a biomarker for disease susceptibility in asymptomatic patients remains to be explored.Last, the authors provide data correlating CD116 expression with STAT3 phosphorylation in response to GM-CSF, suggesting potential functional consequences in cytokine signaling. Overall, the study presents significant promise for CD116 in the assessment and treatment of IBD patients (Figure 2).Figure 2IBD patients exhibit low CD116 levels and low phosphorylated STAT3 in response to GM-CSF.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See page 208.Protection From Hepatitis C Virus InfectionMost patients develop chronic infection after acute exposure to hepatitis C virus (HCV), defined as persistence of serum HCV RNA for >6 months. Chronic persistence of HCV infection predisposes patients to cirrhosis and complications, including hepatocellular carcinoma. However, a minority of patients demonstrate spontaneous clearance after acute exposure. Significant progress has recently been made in understanding the host factors that determine spontaneous resolution of acute hepatitis C infection as well as sustained virologic responses after treatment with pegylated interferon and ribavirin. Genetic variation in and near IL28B, which encodes interferon-λ3, a cytokine with potent in vitro and in vivo antiviral properties, polymorphisms in the IL-12B gene, and homozygosity for the natural killer cell immunoglobulin-like receptor, KIR2DL3, in combination with its ligands, the group 1 HLA-C allotypes, all have been shown to be associated with spontaneous clearance and successful treatment responses.Long-term injection drug users are at high risk for repeated HCV exposure and chronic infection. Yet, a small number of injection drug users do not become viremic or develop antibodies to HCV despite their high-risk behavior. In this issue of Gastroenterology, Knapp et al investigated the genetic factors responsible for this clinical observation. IL28B polymorphism and KIR2DL3:HLA-C group 1 homozygosity were determined in exposed, uninfected (EU) individuals, HCV antibody positive but HCV RNA negative spontaneous resolvers (SR), and HCV antibody and HCV RNA positive chronically infected individuals (Chr). The frequency of the protective IL28B.rs12979860-CC genotype was higher in the SR individuals compared with the Chr group, confirming previous results, but was also higher than in EU individuals, in whom KIRDL3:HLA-C1 was over-represented, distinguishing EU from SR individuals (Table 1). Multivariate logistic regression and a test to determine the synergistic effects of genetic factors demonstrated that these 2 polymorphisms act independently to protect individuals against chronic HCV infection.Table 1Frequency of the IL28B.rs12979860-CC, CT, and TT Genotype in 74 Exposed Uninfected (EU), 89 Spontaneous Resolvers (SR), and 234 Chronic HCV (Chr) Patientsrs12979860 GenotypeEU, n (%)SR, n (%)Chr, n (%)EU vs SREU vs ChrSR vs ChrPOR95% CIPOR95% CIPOR95% CICC31 (41.9)62 (69.7)102 (43.6).0005 (Pc = .002)0.310.16–0.60>.1<.0001 (Pc = .0002)2.971.76–5.00CT32 (43.2)22 (24.7)114 (48.7).019 (Pc = .057)2.321.19–4.52>.1<.0001 (Pc = .0002)0.350.20–0.60TT11 (14.9)5 (5.6)18 (7.7).06 (Pc > .1)2.930.97–8.87.07 (Pc > .1)2.090.94–4.67>.1NOTE. Two tailed P-values were calculated for 2 × 2 contingency tables using a 2-tailed Fisher's exact test, and the Bonferroni correction applied (Pc). Open table in a new tab This study describes 2 distinct populations based on independent genetic factors, individuals who are protected from acute HCV infection based on KIRDL3:HLA-C1 homozygosity and individuals who resolve their acute HCV infection based on IL28B.rs12979860-CC homozygosity.See page 320.Molecular Events in CholangiocarcinomaAlthough it comprises only a small percentage of all primary liver neoplasms, the incidence of cholangiocarcinoma (CCA) is increasing. Risk factors for CCA include primary sclerosing cholangitis, chronic viral hepatitis, and alcoholic and non-alcoholic fatty liver disease. Progress in understanding the molecular pathogenesis of this highly malignant cancer that could lead to the identification of prognostic markers or therapeutic targets has been aided by the development of several animal models, including chemically induced inflammation and cholestatic liver injury from bile duct ligation in rodents. The cell cycle–regulating protein, cyclin D1, a target gene for the transcription factor, c-Myc, is overexpressed in CCA and is associated with dedifferentiation and cell proliferation. Factors that regulate c-Myc effect include binding to the transcription factor, Max, to activate transcription and binding of the c-Myc antagonist, Mnt, to Max to repress transcription. Additional factors include microRNA (miR)-34a and let-7, which are c-Myc–negative regulators; miR-210, which is a negative regulator of Mnt; Lin-28B, a RNA-binding protein that suppresses let-7 expression; and hypoxia, which can up-regulate miRNA-210 via the hypoxia-inducible factors, HIF-1α and HIF2α (Figure 3).Figure 3Transcription factors involved in cholangiocarcinogenesis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In this issue of Gastroenterology, Yang et al use a mouse model that combines inflammation induced by the carcinogen, diethylnitrosamine, and cholestatic liver injury from left and median bile duct ligation to determine the transcription factors that may play a role in the development of CCA. Cholangiofibrosis and CCA formation accelerated in groups treated with both diethylnitrosamine and left and median bile duct ligation. Expression of c-Myc, miR-210, Lin-28B, HIF-1α, and HIF-2α was up-regulated, whereas expression of miR-34a, let-7a, and Mnt was down-regulated in the same groups. Up-regulation of cyclin D1 expression occurred as a result of a switch from Mnt to c-Myc binding in the promoter region of the gene. This switch seems to be important in cholangiocarcinogenesis in this model because administration of Mnt small inhibitor RNA (siRNA), knocking down the effect of Mnt, increased, whereas administration of c-Myc siRNA, in contrast, decreased cholangiofibrosis, ductular cell proliferation, and CCA formation.This study describes the creation of a novel murine model for CCA that may be helpful in unraveling the pathobiology of this all too often rapidly fatal malignancy.See page 378. The Easiest, Cheapest, and Safest WinsPostoperative pancreatic fistulae are a common and troublesome consequence of pancreatic surgery. Most fistulae heal with conservative management, although a variety of therapeutic strategies such as endoscopic intervention, fibrin glues, proton pump inhibitors, and somatostatin analogs have been employed to facilitate healing.The study by Klek et al from the Jagiellonian University Medical in Poland represents a randomized, controlled trial that compares parenterally with enterally administered nutrition on the healing of grade B pancreatic fistulae. Grade B fistulae includes relatively well patients with persistently draining fistulae. Patients with grade C fistulae are clinically less stable and often require aggressive operative intervention for fluid collections and infection in addition to the problems presented by the fistulae. Likewise, grade A fistulae often heal spontaneously with such rapidity that an assessment of different therapies would be difficult. For the class of pancreatic fistulae addressed in this study, the relative efficacy of parenteral or enteral nutrition for fistula healing was unknown.The authors randomized a total of 78 patients to either enteral or parenteral nutrition. The patients were monitored and received an equal number of calories. The results showed a significant advantage for enteral feeding with respect to fistula closure rate, time to healing, and overall costs. The odds ratio for fistula closure within 30 days was 2.6 times higher for enteral versus parenteral feeding. The results indicate that enteral feeding is not only more effective, but also more cost effective and associated with fewer complications.Why enteral nutrition prevailed was not explored, but leading candidates include a number of gastrointestinal hormones and peptides whose release by enteroendocrine cells is stimulated by enteral and not parenteral feeding (Figure 1).See page 157. Postoperative pancreatic fistulae are a common and troublesome consequence of pancreatic surgery. Most fistulae heal with conservative management, although a variety of therapeutic strategies such as endoscopic intervention, fibrin glues, proton pump inhibitors, and somatostatin analogs have been employed to facilitate healing. The study by Klek et al from the Jagiellonian University Medical in Poland represents a randomized, controlled trial that compares parenterally with enterally administered nutrition on the healing of grade B pancreatic fistulae. Grade B fistulae includes relatively well patients with persistently draining fistulae. Patients with grade C fistulae are clinically less stable and often require aggressive operative intervention for fluid collections and infection in addition to the problems presented by the fistulae. Likewise, grade A fistulae often heal spontaneously with such rapidity that an assessment of different therapies would be difficult. For the class of pancreatic fistulae addressed in this study, the relative efficacy of parenteral or enteral nutrition for fistula healing was unknown. The authors randomized a total of 78 patients to either enteral or parenteral nutrition. The patients were monitored and received an equal number of calories. The results showed a significant advantage for enteral feeding with respect to fistula closure rate, time to healing, and overall costs. The odds ratio for fistula closure within 30 days was 2.6 times higher for enteral versus parenteral feeding. The results indicate that enteral feeding is not only more effective, but also more cost effective and associated with fewer complications. Why enteral nutrition prevailed was not explored, but leading candidates include a number of gastrointestinal hormones and peptides whose release by enteroendocrine cells is stimulated by enteral and not parenteral feeding (Figure 1). See page 157. Diagnostic and Functional Implications of CD116 in Inflammatory Bowel DiseaseThe immune system is characterized by adaptive and innate immune responses. The adaptive response is represented by a customized humoral or cell-mediated immune response. In contrast, the innate immune response is nonspecific and includes protective responses by macrophages, granulocytes, and neutrophils. Recent evidence suggests that defects in the innate immune system may serve a significant role in inflammatory bowel disease (IBD). The use of granulocyte-macrophage colony–stimulating factor (GM-CSF) represents one therapeutic approach for IBD that is focused on stimulating the innate immune system. GM-CSF therapy, however, has been characterized by variable clinical outcomes.The study by Goldstein et al focuses on the GM-CSF receptor, CD116, as a potential biomarker for IBD and a role in disease pathogenesis. As a biomarker, quantitative polymerase chain reaction is employed to compare CD116 expression in purified granulocytes from 10 patients with IBD against 10 healthy controls. CD116 mRNA levels were 65% lower among IBD patients compared with controls. Examination of other cytokine receptors showed no difference from controls.The authors extended their study to 52 patients with IBD and an equivalent number of healthy controls by using flow cytometry to quantify CD116 expression on purified monocytes and granulocytes. CD116 mean fluorescent intensities for granulocytes and monocytes were significant lower in IBD patients versus controls (P < .0001). When receiver operating characteristic curves were used to set a minimum threshold, the sensitivity and specificity of CD116 to detect IBD was 90% and 91%, respectively, for granulocytes, and 81% and 94%, respectively, for monocytes. For IBD patients, 82% displayed low CD116 levels in both granulocytes and monocytes, 12% expressed low levels in either granulocytes or monocytes, and 6% had normal levels in both cell lineages. In contrast, 87% of normal healthy controls expressed normal CD116 levels in granulocytes and monocytes, 13% had low levels in either granulocytes or monocytes, and none exhibited low levels in both granulocytes and monocytes. Notable is that CD116 expression was not affected by disease activity or medical treatment. Although more extensive evaluation of other autoimmune and gastrointestinal pathologies is still needed, CD116 demonstrated potential diagnostic power for IBD. The observed heterogeneity in CD116 expression among IBD patients also raises questions of whether it can stratify candidates for GM-CSF therapy. Likewise, whether CD116 is a biomarker for disease susceptibility in asymptomatic patients remains to be explored.Last, the authors provide data correlating CD116 expression with STAT3 phosphorylation in response to GM-CSF, suggesting potential functional consequences in cytokine signaling. Overall, the study presents significant promise for CD116 in the assessment and treatment of IBD patients (Figure 2).See page 208. The immune system is characterized by adaptive and innate immune responses. The adaptive response is represented by a customized humoral or cell-mediated immune response. In contrast, the innate immune response is nonspecific and includes protective responses by macrophages, granulocytes, and neutrophils. Recent evidence suggests that defects in the innate immune system may serve a significant role in inflammatory bowel disease (IBD). The use of granulocyte-macrophage colony–stimulating factor (GM-CSF) represents one therapeutic approach for IBD that is focused on stimulating the innate immune system. GM-CSF therapy, however, has been characterized by variable clinical outcomes. The study by Goldstein et al focuses on the GM-CSF receptor, CD116, as a potential biomarker for IBD and a role in disease pathogenesis. As a biomarker, quantitative polymerase chain reaction is employed to compare CD116 expression in purified granulocytes from 10 patients with IBD against 10 healthy controls. CD116 mRNA levels were 65% lower among IBD patients compared with controls. Examination of other cytokine receptors showed no difference from controls. The authors extended their study to 52 patients with IBD and an equivalent number of healthy controls by using flow cytometry to quantify CD116 expression on purified monocytes and granulocytes. CD116 mean fluorescent intensities for granulocytes and monocytes were significant lower in IBD patients versus controls (P < .0001). When receiver operating characteristic curves were used to set a minimum threshold, the sensitivity and specificity of CD116 to detect IBD was 90% and 91%, respectively, for granulocytes, and 81% and 94%, respectively, for monocytes. For IBD patients, 82% displayed low CD116 levels in both granulocytes and monocytes, 12% expressed low levels in either granulocytes or monocytes, and 6% had normal levels in both cell lineages. In contrast, 87% of normal healthy controls expressed normal CD116 levels in granulocytes and monocytes, 13% had low levels in either granulocytes or monocytes, and none exhibited low levels in both granulocytes and monocytes. Notable is that CD116 expression was not affected by disease activity or medical treatment. Although more extensive evaluation of other autoimmune and gastrointestinal pathologies is still needed, CD116 demonstrated potential diagnostic power for IBD. The observed heterogeneity in CD116 expression among IBD patients also raises questions of whether it can stratify candidates for GM-CSF therapy. Likewise, whether CD116 is a biomarker for disease susceptibility in asymptomatic patients remains to be explored. Last, the authors provide data correlating CD116 expression with STAT3 phosphorylation in response to GM-CSF, suggesting potential functional consequences in cytokine signaling. Overall, the study presents significant promise for CD116 in the assessment and treatment of IBD patients (Figure 2). See page 208. Protection From Hepatitis C Virus InfectionMost patients develop chronic infection after acute exposure to hepatitis C virus (HCV), defined as persistence of serum HCV RNA for >6 months. Chronic persistence of HCV infection predisposes patients to cirrhosis and complications, including hepatocellular carcinoma. However, a minority of patients demonstrate spontaneous clearance after acute exposure. Significant progress has recently been made in understanding the host factors that determine spontaneous resolution of acute hepatitis C infection as well as sustained virologic responses after treatment with pegylated interferon and ribavirin. Genetic variation in and near IL28B, which encodes interferon-λ3, a cytokine with potent in vitro and in vivo antiviral properties, polymorphisms in the IL-12B gene, and homozygosity for the natural killer cell immunoglobulin-like receptor, KIR2DL3, in combination with its ligands, the group 1 HLA-C allotypes, all have been shown to be associated with spontaneous clearance and successful treatment responses.Long-term injection drug users are at high risk for repeated HCV exposure and chronic infection. Yet, a small number of injection drug users do not become viremic or develop antibodies to HCV despite their high-risk behavior. In this issue of Gastroenterology, Knapp et al investigated the genetic factors responsible for this clinical observation. IL28B polymorphism and KIR2DL3:HLA-C group 1 homozygosity were determined in exposed, uninfected (EU) individuals, HCV antibody positive but HCV RNA negative spontaneous resolvers (SR), and HCV antibody and HCV RNA positive chronically infected individuals (Chr). The frequency of the protective IL28B.rs12979860-CC genotype was higher in the SR individuals compared with the Chr group, confirming previous results, but was also higher than in EU individuals, in whom KIRDL3:HLA-C1 was over-represented, distinguishing EU from SR individuals (Table 1). Multivariate logistic regression and a test to determine the synergistic effects of genetic factors demonstrated that these 2 polymorphisms act independently to protect individuals against chronic HCV infection.Table 1Frequency of the IL28B.rs12979860-CC, CT, and TT Genotype in 74 Exposed Uninfected (EU), 89 Spontaneous Resolvers (SR), and 234 Chronic HCV (Chr) Patientsrs12979860 GenotypeEU, n (%)SR, n (%)Chr, n (%)EU vs SREU vs ChrSR vs ChrPOR95% CIPOR95% CIPOR95% CICC31 (41.9)62 (69.7)102 (43.6).0005 (Pc = .002)0.310.16–0.60>.1<.0001 (Pc = .0002)2.971.76–5.00CT32 (43.2)22 (24.7)114 (48.7).019 (Pc = .057)2.321.19–4.52>.1<.0001 (Pc = .0002)0.350.20–0.60TT11 (14.9)5 (5.6)18 (7.7).06 (Pc > .1)2.930.97–8.87.07 (Pc > .1)2.090.94–4.67>.1NOTE. Two tailed P-values were calculated for 2 × 2 contingency tables using a 2-tailed Fisher's exact test, and the Bonferroni correction applied (Pc). Open table in a new tab This study describes 2 distinct populations based on independent genetic factors, individuals who are protected from acute HCV infection based on KIRDL3:HLA-C1 homozygosity and individuals who resolve their acute HCV infection based on IL28B.rs12979860-CC homozygosity.See page 320. Most patients develop chronic infection after acute exposure to hepatitis C virus (HCV), defined as persistence of serum HCV RNA for >6 months. Chronic persistence of HCV infection predisposes patients to cirrhosis and complications, including hepatocellular carcinoma. However, a minority of patients demonstrate spontaneous clearance after acute exposure. Significant progress has recently been made in understanding the host factors that determine spontaneous resolution of acute hepatitis C infection as well as sustained virologic responses after treatment with pegylated interferon and ribavirin. Genetic variation in and near IL28B, which encodes interferon-λ3, a cytokine with potent in vitro and in vivo antiviral properties, polymorphisms in the IL-12B gene, and homozygosity for the natural killer cell immunoglobulin-like receptor, KIR2DL3, in combination with its ligands, the group 1 HLA-C allotypes, all have been shown to be associated with spontaneous clearance and successful treatment responses. Long-term injection drug users are at high risk for repeated HCV exposure and chronic infection. Yet, a small number of injection drug users do not become viremic or develop antibodies to HCV despite their high-risk behavior. In this issue of Gastroenterology, Knapp et al investigated the genetic factors responsible for this clinical observation. IL28B polymorphism and KIR2DL3:HLA-C group 1 homozygosity were determined in exposed, uninfected (EU) individuals, HCV antibody positive but HCV RNA negative spontaneous resolvers (SR), and HCV antibody and HCV RNA positive chronically infected individuals (Chr). The frequency of the protective IL28B.rs12979860-CC genotype was higher in the SR individuals compared with the Chr group, confirming previous results, but was also higher than in EU individuals, in whom KIRDL3:HLA-C1 was over-represented, distinguishing EU from SR individuals (Table 1). Multivariate logistic regression and a test to determine the synergistic effects of genetic factors demonstrated that these 2 polymorphisms act independently to protect individuals against chronic HCV infection. NOTE. Two tailed P-values were calculated for 2 × 2 contingency tables using a 2-tailed Fisher's exact test, and the Bonferroni correction applied (Pc). This study describes 2 distinct populations based on independent genetic factors, individuals who are protected from acute HCV infection based on KIRDL3:HLA-C1 homozygosity and individuals who resolve their acute HCV infection based on IL28B.rs12979860-CC homozygosity. See page 320. Molecular Events in CholangiocarcinomaAlthough it comprises only a small percentage of all primary liver neoplasms, the incidence of cholangiocarcinoma (CCA) is increasing. Risk factors for CCA include primary sclerosing cholangitis, chronic viral hepatitis, and alcoholic and non-alcoholic fatty liver disease. Progress in understanding the molecular pathogenesis of this highly malignant cancer that could lead to the identification of prognostic markers or therapeutic targets has been aided by the development of several animal models, including chemically induced inflammation and cholestatic liver injury from bile duct ligation in rodents. The cell cycle–regulating protein, cyclin D1, a target gene for the transcription factor, c-Myc, is overexpressed in CCA and is associated with dedifferentiation and cell proliferation. Factors that regulate c-Myc effect include binding to the transcription factor, Max, to activate transcription and binding of the c-Myc antagonist, Mnt, to Max to repress transcription. Additional factors include microRNA (miR)-34a and let-7, which are c-Myc–negative regulators; miR-210, which is a negative regulator of Mnt; Lin-28B, a RNA-binding protein that suppresses let-7 expression; and hypoxia, which can up-regulate miRNA-210 via the hypoxia-inducible factors, HIF-1α and HIF2α (Figure 3).In this issue of Gastroenterology, Yang et al use a mouse model that combines inflammation induced by the carcinogen, diethylnitrosamine, and cholestatic liver injury from left and median bile duct ligation to determine the transcription factors that may play a role in the development of CCA. Cholangiofibrosis and CCA formation accelerated in groups treated with both diethylnitrosamine and left and median bile duct ligation. Expression of c-Myc, miR-210, Lin-28B, HIF-1α, and HIF-2α was up-regulated, whereas expression of miR-34a, let-7a, and Mnt was down-regulated in the same groups. Up-regulation of cyclin D1 expression occurred as a result of a switch from Mnt to c-Myc binding in the promoter region of the gene. This switch seems to be important in cholangiocarcinogenesis in this model because administration of Mnt small inhibitor RNA (siRNA), knocking down the effect of Mnt, increased, whereas administration of c-Myc siRNA, in contrast, decreased cholangiofibrosis, ductular cell proliferation, and CCA formation.This study describes the creation of a novel murine model for CCA that may be helpful in unraveling the pathobiology of this all too often rapidly fatal malignancy.See page 378. Although it comprises only a small percentage of all primary liver neoplasms, the incidence of cholangiocarcinoma (CCA) is increasing. Risk factors for CCA include primary sclerosing cholangitis, chronic viral hepatitis, and alcoholic and non-alcoholic fatty liver disease. Progress in understanding the molecular pathogenesis of this highly malignant cancer that could lead to the identification of prognostic markers or therapeutic targets has been aided by the development of several animal models, including chemically induced inflammation and cholestatic liver injury from bile duct ligation in rodents. The cell cycle–regulating protein, cyclin D1, a target gene for the transcription factor, c-Myc, is overexpressed in CCA and is associated with dedifferentiation and cell proliferation. Factors that regulate c-Myc effect include binding to the transcription factor, Max, to activate transcription and binding of the c-Myc antagonist, Mnt, to Max to repress transcription. Additional factors include microRNA (miR)-34a and let-7, which are c-Myc–negative regulators; miR-210, which is a negative regulator of Mnt; Lin-28B, a RNA-binding protein that suppresses let-7 expression; and hypoxia, which can up-regulate miRNA-210 via the hypoxia-inducible factors, HIF-1α and HIF2α (Figure 3). In this issue of Gastroenterology, Yang et al use a mouse model that combines inflammation induced by the carcinogen, diethylnitrosamine, and cholestatic liver injury from left and median bile duct ligation to determine the transcription factors that may play a role in the development of CCA. Cholangiofibrosis and CCA formation accelerated in groups treated with both diethylnitrosamine and left and median bile duct ligation. Expression of c-Myc, miR-210, Lin-28B, HIF-1α, and HIF-2α was up-regulated, whereas expression of miR-34a, let-7a, and Mnt was down-regulated in the same groups. Up-regulation of cyclin D1 expression occurred as a result of a switch from Mnt to c-Myc binding in the promoter region of the gene. This switch seems to be important in cholangiocarcinogenesis in this model because administration of Mnt small inhibitor RNA (siRNA), knocking down the effect of Mnt, increased, whereas administration of c-Myc siRNA, in contrast, decreased cholangiofibrosis, ductular cell proliferation, and CCA formation. This study describes the creation of a novel murine model for CCA that may be helpful in unraveling the pathobiology of this all too often rapidly fatal malignancy. See page 378.