Heritability of Hepatic Fibrosis and SteatosisNonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and progression to its more advanced form, nonalcoholic steatohepatitis, leads to progressive fibrosis, cirrhosis, and its complications, including hepatocellular carcinoma and the need for liver transplantation. Previous studies demonstrating a link between PNPLA-3 genotype and hepatic steatosis and features of nonalcoholic steatohepatitis have suggested a genetic predisposition to NAFLD. However, PNPLA-3 genotype accounts for only a small variance in the trait and there are no systematic examinations of the heritability of NAFLD-associated hepatic steatosis or hepatic fibrosis. In this issue of Gastroenterology, Loomba et al describe their results of a cross-sectional analysis of 60 pairs of twins (42 monozygotic and 18 dizygotic) from urban Southern California to determine whether hepatic steatosis and/or hepatic fibrosis are heritable traits. Hepatic steatosis was noninvasively quantified by MRI and determined by the proton-density fat fraction (MRI-PDFF), previously found to be superior to ultrasonography and computed tomography in the quantification of liver fat content. Hepatic fibrosis was determined noninvasively by stiffness on magnetic resonance elastography (MRE), a test also previously found to be superior to ultrasonography and 8 clinical prediction rules in the quantification of hepatic fibrosis. The prevalence of NAFLD in this twin cohort was 21.7% (26/120). Pairs of monozygotic twins demonstrated a significant correlation (0.70) in hepatic steatosis as measured by MRI-PDFF; pairs of dizygotic twins did not. Pairs of monozygotic twins also demonstrated a significant correlation (0.48) in hepatic fibrosis as measured by MRE-stiffness; pairs of dizygotic twins did not (Figure 1). In multivariable models adjusted for age, sex, and ethnicity, the heritability of steatosis and hepatic fibrosis was 0.52 and 0.5, respectively. Models that included PNPLA3 genotype suggested that this genotype was not a significant predictor of MRI-PDFF or MRE stiffness, although the study may have been underpowered to detect an effect of this genotype. These novel findings suggest that both hepatic steatosis and hepatic fibrosis are heritable traits and may have important implications in the development of targeted approaches to NAFLD-related fibrosis.See page 1784.Portal Sampling of Pancreatobiliary Circulating Tumor Cells by Endoscopic UltrasonographyPancreatic cancer remains among the leading causes of cancer-related death. There is a significant effort focused on approaches that will lead to earlier diagnosis or the identification of patients best suited for different treatment modalities. One approach that has attracted considerable attention is the identification of circulating tumor cells (CTCs). CTCs have been isolated from the bloodstream of cancer patients and potentially are detectable before the appearance of the primary tumor.The site where blood is obtained may impact the yield for detecting CTCs derived from gastrointestinal tumors. Because the gastrointestinal tract's venous drainage first passes through the liver, the organ is often the site of metastasis. The liver may also serve as a filter that prevents CTCs from reaching the systemic vasculature. In fact, previous studies of colorectal cancer patients determined that higher numbers of CTCs were obtained from blood harvested directly from the portal vein during surgery in contrast with that obtained from the peripheral veins.In this issue of Gastroenterology, Catenacci et al report on a less invasive approach for isolating CTCs from the portal vein with endoscopic ultrasonography. Patients with surgically resectable and unresectable pancreaticobiliary cancers comprised the study population. Blood was obtained from the portal vein with a 19-G needle during endoscopic ultrasonography. Two to four 8.5-mL aliquots of blood were obtained from each patient. Among the 18 patients studied, there were no complications with the portal vein sampling.CTCs were isolated from the portal vein and peripheral venous blood by first labeling the cells with ferromagnetic labeled antibodies against EpCam, a membrane protein that is expressed on many epithelial cancers. The cells were then further characterized for features consistent with pancreaticobiliary cancers, which included the presence of cytokeratins 8, 18, and/or 19, and the absence of CD45.CTCs were detected in portal vein samples from all patients with pancreaticobiliary cancer, but in only 25% of peripheral blood samples from the same patients. In addition, the CTC yield was significantly greater in the portal vein samples (Figure 2). The authors also demonstrated that additional analyses of the CTCs were possible, and included changes in protein expression that are indicative of mutations in TP53, SMAD4, and p16/CDKN2A. The authors establish that endoscopic ultrasonography is a viable approach for portal vein sampling. They propose that enumerating CTCs and the ability to analyze mutations may help stratify patients in the future with respect to prognosis and/or choosing the appropriate therapies.Figure 2Yield of CTCs obtained from endoscopic ultrasonography-mediated portal vein samples compared with those from peripheral veins.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See page 1794.Activating GLI Mutations in Patients With Hirschsprung DiseaseHirschsprung disease, or aganglionic megacolon, is a heterogeneous genetic disorder thought to be the result of a failure of enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog signaling has been shown previously to be a key factor in the proliferation, migration, and differentiation of ENCCs. In addition, Sox10 (a transcription factor critical to enteric nervous system differentiation), Gli1, Gli2, and Gli3 (transcription factors involved in Hedgehog signaling), and Suppressor of Fused (Sufu; a negative regulator of Gli transcription factors) have all been previously considered to have a role in the pathogenesis of Hirschsprung disease. In this issue of Gastroenterology (accompanied by an editorial by Heather Young and Robert Hofstra), Liu et al further explore the role of the SOX10–SUFU–GLI regulatory nexus in the development of the enteric nervous system and the pathogenesis of Hirschsprung disease. Using targeted sequencing in 20 patients with sporadic Hirschsprung disease, 4 heterozygous missense mutations in the coding sequence of GLI1, GLI2, and GLI3 were identified in 5 patients but not in controls. Luciferase reporter assays demonstrated that all mutations led to increased activity of GLI proteins. Constitutively high Gli activity in Sufu mutant mice resulted in early onset of ENCC differentiation in vitro, with a greater number of glial cells and decreased numbers of neurons being developed, a ratio that may result in gut dysmotility. Severe axonal fasciculation defects were observed in the gut of Sufu mutant mice and neurons derived from these mice exhibited similar defects with thinner nerve fibers as well as disrupted directional migration. Sufu mutant mice demonstrated elevated Sox10 expression and Sufu, through control of Gli transcriptional activity, was found to negatively regulate Sox10 expression in ENCCs. Reduction of levels of Sox10 attenuated the aberrant glial differentiation in Sufu mutant mice. This study identifies for the first time GLI mutations in patients with Hirschsprung disease and provides novel insight into the role of the Sox10–Sufu–Gli regulatory nexus in ENCC differentiation and migration during the development of the enteric nervous system (Figure 3).Figure 3Sufu, Gli, and Sox10 work coordinately to mediate gliogenesis of enteric NCCs. Schematic diagram illustrates the regulatory loop among Sufu, Gli, and Sox10 involved in mediating gliogenesis of enteric NCCs.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See page 1837; editorial on page 1672.Neutrophil Extracellular Traps as Potential Therapy Targets for Acute PancreatitisNeutrophils participate in the defense against bacteria through phagocytosis and subsequent intracellular destruction with proteolytic enzymes. Neutrophils, however, are also capable of killing pathogens in the extracellular space through a process known as neutrophil extracellular traps (NETs). NETs consists of an extracellular network of DNA, histones, and granule proteins expelled from neutrophils that serve to trap bacteria. Elastase and other granule proteins within the NETs kill the bacteria. The bactericidal effects of NETs are destroyed if the DNA-containing webs are destroyed with DNase. NETs are therefore considered a beneficial form on innate immunity.In this issue of Gastroenterology, Merza et al from Lund University in Sweden report on their studies of NETs in acute pancreatitis. Acute pancreatitis is an inflammatory process in which severe cases are associated with mortality rates of up to 25%. Neutrophils are recruited to the site of the pancreatitis, but their presence may be potentially deleterious instead of beneficial. Prior studies have shown that interruption of neutrophil recruitment to the site of pancreatitis ameliorates tissue damage.Using 2 different models of murine experimental pancreatitis, Merza et al demonstrated that neutrophil-associated NETs worsen the course of pancreatitis. They first employed scanning electron microscopy to establish the presence of NETs in pancreatitis induced with either taurocholate or l-arginine (Figure 4). The authors then destroyed the NETs with DNase, which ameliorated the acute pancreatitis as measured by serum amylase levels or the proinflammatory factors interleukin-6 and HMGB1. NETs were also associated with trypsinogen activation to trypsin, which serves an important role in pancreatitis pathogenesis. This effect was also lost after DNase treatment.Figure 4Neutrophil extracellular traps in taurocholate-induced pancreatitis, but not after treatment with DNase. Saline is the control without pancreatitis. PMN, polymorphonuclear neutrophils.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The authors concluded that development of NET-targeted therapies represents a promising approach for pancreatitis treatment. An accompanying editorial by Ashok Saluja and Paul Kubes provides further insights on this work.See page 1920; editorial on page 1682. Heritability of Hepatic Fibrosis and SteatosisNonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and progression to its more advanced form, nonalcoholic steatohepatitis, leads to progressive fibrosis, cirrhosis, and its complications, including hepatocellular carcinoma and the need for liver transplantation. Previous studies demonstrating a link between PNPLA-3 genotype and hepatic steatosis and features of nonalcoholic steatohepatitis have suggested a genetic predisposition to NAFLD. However, PNPLA-3 genotype accounts for only a small variance in the trait and there are no systematic examinations of the heritability of NAFLD-associated hepatic steatosis or hepatic fibrosis. In this issue of Gastroenterology, Loomba et al describe their results of a cross-sectional analysis of 60 pairs of twins (42 monozygotic and 18 dizygotic) from urban Southern California to determine whether hepatic steatosis and/or hepatic fibrosis are heritable traits. Hepatic steatosis was noninvasively quantified by MRI and determined by the proton-density fat fraction (MRI-PDFF), previously found to be superior to ultrasonography and computed tomography in the quantification of liver fat content. Hepatic fibrosis was determined noninvasively by stiffness on magnetic resonance elastography (MRE), a test also previously found to be superior to ultrasonography and 8 clinical prediction rules in the quantification of hepatic fibrosis. The prevalence of NAFLD in this twin cohort was 21.7% (26/120). Pairs of monozygotic twins demonstrated a significant correlation (0.70) in hepatic steatosis as measured by MRI-PDFF; pairs of dizygotic twins did not. Pairs of monozygotic twins also demonstrated a significant correlation (0.48) in hepatic fibrosis as measured by MRE-stiffness; pairs of dizygotic twins did not (Figure 1). In multivariable models adjusted for age, sex, and ethnicity, the heritability of steatosis and hepatic fibrosis was 0.52 and 0.5, respectively. Models that included PNPLA3 genotype suggested that this genotype was not a significant predictor of MRI-PDFF or MRE stiffness, although the study may have been underpowered to detect an effect of this genotype. These novel findings suggest that both hepatic steatosis and hepatic fibrosis are heritable traits and may have important implications in the development of targeted approaches to NAFLD-related fibrosis.See page 1784. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and progression to its more advanced form, nonalcoholic steatohepatitis, leads to progressive fibrosis, cirrhosis, and its complications, including hepatocellular carcinoma and the need for liver transplantation. Previous studies demonstrating a link between PNPLA-3 genotype and hepatic steatosis and features of nonalcoholic steatohepatitis have suggested a genetic predisposition to NAFLD. However, PNPLA-3 genotype accounts for only a small variance in the trait and there are no systematic examinations of the heritability of NAFLD-associated hepatic steatosis or hepatic fibrosis. In this issue of Gastroenterology, Loomba et al describe their results of a cross-sectional analysis of 60 pairs of twins (42 monozygotic and 18 dizygotic) from urban Southern California to determine whether hepatic steatosis and/or hepatic fibrosis are heritable traits. Hepatic steatosis was noninvasively quantified by MRI and determined by the proton-density fat fraction (MRI-PDFF), previously found to be superior to ultrasonography and computed tomography in the quantification of liver fat content. Hepatic fibrosis was determined noninvasively by stiffness on magnetic resonance elastography (MRE), a test also previously found to be superior to ultrasonography and 8 clinical prediction rules in the quantification of hepatic fibrosis. The prevalence of NAFLD in this twin cohort was 21.7% (26/120). Pairs of monozygotic twins demonstrated a significant correlation (0.70) in hepatic steatosis as measured by MRI-PDFF; pairs of dizygotic twins did not. Pairs of monozygotic twins also demonstrated a significant correlation (0.48) in hepatic fibrosis as measured by MRE-stiffness; pairs of dizygotic twins did not (Figure 1). In multivariable models adjusted for age, sex, and ethnicity, the heritability of steatosis and hepatic fibrosis was 0.52 and 0.5, respectively. Models that included PNPLA3 genotype suggested that this genotype was not a significant predictor of MRI-PDFF or MRE stiffness, although the study may have been underpowered to detect an effect of this genotype. These novel findings suggest that both hepatic steatosis and hepatic fibrosis are heritable traits and may have important implications in the development of targeted approaches to NAFLD-related fibrosis. See page 1784. Portal Sampling of Pancreatobiliary Circulating Tumor Cells by Endoscopic UltrasonographyPancreatic cancer remains among the leading causes of cancer-related death. There is a significant effort focused on approaches that will lead to earlier diagnosis or the identification of patients best suited for different treatment modalities. One approach that has attracted considerable attention is the identification of circulating tumor cells (CTCs). CTCs have been isolated from the bloodstream of cancer patients and potentially are detectable before the appearance of the primary tumor.The site where blood is obtained may impact the yield for detecting CTCs derived from gastrointestinal tumors. Because the gastrointestinal tract's venous drainage first passes through the liver, the organ is often the site of metastasis. The liver may also serve as a filter that prevents CTCs from reaching the systemic vasculature. In fact, previous studies of colorectal cancer patients determined that higher numbers of CTCs were obtained from blood harvested directly from the portal vein during surgery in contrast with that obtained from the peripheral veins.In this issue of Gastroenterology, Catenacci et al report on a less invasive approach for isolating CTCs from the portal vein with endoscopic ultrasonography. Patients with surgically resectable and unresectable pancreaticobiliary cancers comprised the study population. Blood was obtained from the portal vein with a 19-G needle during endoscopic ultrasonography. Two to four 8.5-mL aliquots of blood were obtained from each patient. Among the 18 patients studied, there were no complications with the portal vein sampling.CTCs were isolated from the portal vein and peripheral venous blood by first labeling the cells with ferromagnetic labeled antibodies against EpCam, a membrane protein that is expressed on many epithelial cancers. The cells were then further characterized for features consistent with pancreaticobiliary cancers, which included the presence of cytokeratins 8, 18, and/or 19, and the absence of CD45.CTCs were detected in portal vein samples from all patients with pancreaticobiliary cancer, but in only 25% of peripheral blood samples from the same patients. In addition, the CTC yield was significantly greater in the portal vein samples (Figure 2). The authors also demonstrated that additional analyses of the CTCs were possible, and included changes in protein expression that are indicative of mutations in TP53, SMAD4, and p16/CDKN2A. The authors establish that endoscopic ultrasonography is a viable approach for portal vein sampling. They propose that enumerating CTCs and the ability to analyze mutations may help stratify patients in the future with respect to prognosis and/or choosing the appropriate therapies.See page 1794. Pancreatic cancer remains among the leading causes of cancer-related death. There is a significant effort focused on approaches that will lead to earlier diagnosis or the identification of patients best suited for different treatment modalities. One approach that has attracted considerable attention is the identification of circulating tumor cells (CTCs). CTCs have been isolated from the bloodstream of cancer patients and potentially are detectable before the appearance of the primary tumor. The site where blood is obtained may impact the yield for detecting CTCs derived from gastrointestinal tumors. Because the gastrointestinal tract's venous drainage first passes through the liver, the organ is often the site of metastasis. The liver may also serve as a filter that prevents CTCs from reaching the systemic vasculature. In fact, previous studies of colorectal cancer patients determined that higher numbers of CTCs were obtained from blood harvested directly from the portal vein during surgery in contrast with that obtained from the peripheral veins. In this issue of Gastroenterology, Catenacci et al report on a less invasive approach for isolating CTCs from the portal vein with endoscopic ultrasonography. Patients with surgically resectable and unresectable pancreaticobiliary cancers comprised the study population. Blood was obtained from the portal vein with a 19-G needle during endoscopic ultrasonography. Two to four 8.5-mL aliquots of blood were obtained from each patient. Among the 18 patients studied, there were no complications with the portal vein sampling. CTCs were isolated from the portal vein and peripheral venous blood by first labeling the cells with ferromagnetic labeled antibodies against EpCam, a membrane protein that is expressed on many epithelial cancers. The cells were then further characterized for features consistent with pancreaticobiliary cancers, which included the presence of cytokeratins 8, 18, and/or 19, and the absence of CD45. CTCs were detected in portal vein samples from all patients with pancreaticobiliary cancer, but in only 25% of peripheral blood samples from the same patients. In addition, the CTC yield was significantly greater in the portal vein samples (Figure 2). The authors also demonstrated that additional analyses of the CTCs were possible, and included changes in protein expression that are indicative of mutations in TP53, SMAD4, and p16/CDKN2A. The authors establish that endoscopic ultrasonography is a viable approach for portal vein sampling. They propose that enumerating CTCs and the ability to analyze mutations may help stratify patients in the future with respect to prognosis and/or choosing the appropriate therapies. See page 1794. Activating GLI Mutations in Patients With Hirschsprung DiseaseHirschsprung disease, or aganglionic megacolon, is a heterogeneous genetic disorder thought to be the result of a failure of enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog signaling has been shown previously to be a key factor in the proliferation, migration, and differentiation of ENCCs. In addition, Sox10 (a transcription factor critical to enteric nervous system differentiation), Gli1, Gli2, and Gli3 (transcription factors involved in Hedgehog signaling), and Suppressor of Fused (Sufu; a negative regulator of Gli transcription factors) have all been previously considered to have a role in the pathogenesis of Hirschsprung disease. In this issue of Gastroenterology (accompanied by an editorial by Heather Young and Robert Hofstra), Liu et al further explore the role of the SOX10–SUFU–GLI regulatory nexus in the development of the enteric nervous system and the pathogenesis of Hirschsprung disease. Using targeted sequencing in 20 patients with sporadic Hirschsprung disease, 4 heterozygous missense mutations in the coding sequence of GLI1, GLI2, and GLI3 were identified in 5 patients but not in controls. Luciferase reporter assays demonstrated that all mutations led to increased activity of GLI proteins. Constitutively high Gli activity in Sufu mutant mice resulted in early onset of ENCC differentiation in vitro, with a greater number of glial cells and decreased numbers of neurons being developed, a ratio that may result in gut dysmotility. Severe axonal fasciculation defects were observed in the gut of Sufu mutant mice and neurons derived from these mice exhibited similar defects with thinner nerve fibers as well as disrupted directional migration. Sufu mutant mice demonstrated elevated Sox10 expression and Sufu, through control of Gli transcriptional activity, was found to negatively regulate Sox10 expression in ENCCs. Reduction of levels of Sox10 attenuated the aberrant glial differentiation in Sufu mutant mice. This study identifies for the first time GLI mutations in patients with Hirschsprung disease and provides novel insight into the role of the Sox10–Sufu–Gli regulatory nexus in ENCC differentiation and migration during the development of the enteric nervous system (Figure 3).See page 1837; editorial on page 1672. Hirschsprung disease, or aganglionic megacolon, is a heterogeneous genetic disorder thought to be the result of a failure of enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog signaling has been shown previously to be a key factor in the proliferation, migration, and differentiation of ENCCs. In addition, Sox10 (a transcription factor critical to enteric nervous system differentiation), Gli1, Gli2, and Gli3 (transcription factors involved in Hedgehog signaling), and Suppressor of Fused (Sufu; a negative regulator of Gli transcription factors) have all been previously considered to have a role in the pathogenesis of Hirschsprung disease. In this issue of Gastroenterology (accompanied by an editorial by Heather Young and Robert Hofstra), Liu et al further explore the role of the SOX10–SUFU–GLI regulatory nexus in the development of the enteric nervous system and the pathogenesis of Hirschsprung disease. Using targeted sequencing in 20 patients with sporadic Hirschsprung disease, 4 heterozygous missense mutations in the coding sequence of GLI1, GLI2, and GLI3 were identified in 5 patients but not in controls. Luciferase reporter assays demonstrated that all mutations led to increased activity of GLI proteins. Constitutively high Gli activity in Sufu mutant mice resulted in early onset of ENCC differentiation in vitro, with a greater number of glial cells and decreased numbers of neurons being developed, a ratio that may result in gut dysmotility. Severe axonal fasciculation defects were observed in the gut of Sufu mutant mice and neurons derived from these mice exhibited similar defects with thinner nerve fibers as well as disrupted directional migration. Sufu mutant mice demonstrated elevated Sox10 expression and Sufu, through control of Gli transcriptional activity, was found to negatively regulate Sox10 expression in ENCCs. Reduction of levels of Sox10 attenuated the aberrant glial differentiation in Sufu mutant mice. This study identifies for the first time GLI mutations in patients with Hirschsprung disease and provides novel insight into the role of the Sox10–Sufu–Gli regulatory nexus in ENCC differentiation and migration during the development of the enteric nervous system (Figure 3). See page 1837; editorial on page 1672. Neutrophil Extracellular Traps as Potential Therapy Targets for Acute PancreatitisNeutrophils participate in the defense against bacteria through phagocytosis and subsequent intracellular destruction with proteolytic enzymes. Neutrophils, however, are also capable of killing pathogens in the extracellular space through a process known as neutrophil extracellular traps (NETs). NETs consists of an extracellular network of DNA, histones, and granule proteins expelled from neutrophils that serve to trap bacteria. Elastase and other granule proteins within the NETs kill the bacteria. The bactericidal effects of NETs are destroyed if the DNA-containing webs are destroyed with DNase. NETs are therefore considered a beneficial form on innate immunity.In this issue of Gastroenterology, Merza et al from Lund University in Sweden report on their studies of NETs in acute pancreatitis. Acute pancreatitis is an inflammatory process in which severe cases are associated with mortality rates of up to 25%. Neutrophils are recruited to the site of the pancreatitis, but their presence may be potentially deleterious instead of beneficial. Prior studies have shown that interruption of neutrophil recruitment to the site of pancreatitis ameliorates tissue damage.Using 2 different models of murine experimental pancreatitis, Merza et al demonstrated that neutrophil-associated NETs worsen the course of pancreatitis. They first employed scanning electron microscopy to establish the presence of NETs in pancreatitis induced with either taurocholate or l-arginine (Figure 4). The authors then destroyed the NETs with DNase, which ameliorated the acute pancreatitis as measured by serum amylase levels or the proinflammatory factors interleukin-6 and HMGB1. NETs were also associated with trypsinogen activation to trypsin, which serves an important role in pancreatitis pathogenesis. This effect was also lost after DNase treatment.The authors concluded that development of NET-targeted therapies represents a promising approach for pancreatitis treatment. An accompanying editorial by Ashok Saluja and Paul Kubes provides further insights on this work.See page 1920; editorial on page 1682. Neutrophils participate in the defense against bacteria through phagocytosis and subsequent intracellular destruction with proteolytic enzymes. Neutrophils, however, are also capable of killing pathogens in the extracellular space through a process known as neutrophil extracellular traps (NETs). NETs consists of an extracellular network of DNA, histones, and granule proteins expelled from neutrophils that serve to trap bacteria. Elastase and other granule proteins within the NETs kill the bacteria. The bactericidal effects of NETs are destroyed if the DNA-containing webs are destroyed with DNase. NETs are therefore considered a beneficial form on innate immunity. In this issue of Gastroenterology, Merza et al from Lund University in Sweden report on their studies of NETs in acute pancreatitis. Acute pancreatitis is an inflammatory process in which severe cases are associated with mortality rates of up to 25%. Neutrophils are recruited to the site of the pancreatitis, but their presence may be potentially deleterious instead of beneficial. Prior studies have shown that interruption of neutrophil recruitment to the site of pancreatitis ameliorates tissue damage. Using 2 different models of murine experimental pancreatitis, Merza et al demonstrated that neutrophil-associated NETs worsen the course of pancreatitis. They first employed scanning electron microscopy to establish the presence of NETs in pancreatitis induced with either taurocholate or l-arginine (Figure 4). The authors then destroyed the NETs with DNase, which ameliorated the acute pancreatitis as measured by serum amylase levels or the proinflammatory factors interleukin-6 and HMGB1. NETs were also associated with trypsinogen activation to trypsin, which serves an important role in pancreatitis pathogenesis. This effect was also lost after DNase treatment. The authors concluded that development of NET-targeted therapies represents a promising approach for pancreatitis treatment. An accompanying editorial by Ashok Saluja and Paul Kubes provides further insights on this work. See page 1920; editorial on page 1682. Neutrophil Extracellular Traps Induce Trypsin Activation, Inflammation, and Tissue Damage in Mice With Severe Acute PancreatitisGastroenterologyVol. 149Issue 7PreviewNeutrophils are involved in the development of acute pancreatitis (AP), but it is not clear how neutrophil-induced tissue damage is regulated. In addition to secreting antimicrobial compounds, activated neutrophils eliminate invading microorganisms by expelling nuclear DNA and histones to form extracellular web-like structures called neutrophil extracellular traps (NETs). However, NETs have been reported to contribute to organ dysfunction in patients with infectious diseases. We investigated whether NETs contribute to the development of AP in mice. Full-Text PDF Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin StudyGastroenterologyVol. 149Issue 7PreviewLittle is known about the heritability of hepatic fibrosis, and the heritability of hepatic steatosis has not been assessed systematically in adults. We investigated the heritability of hepatic fibrosis and steatosis in a community-dwelling twin cohort. Full-Text PDF Acquisition of Portal Venous Circulating Tumor Cells From Patients With Pancreaticobiliary Cancers by Endoscopic UltrasoundGastroenterologyVol. 149Issue 7PreviewTumor cells circulate in low numbers in peripheral blood; their detection is used predominantly in metastatic disease. We evaluated the feasibility and safety of sampling portal venous blood via endoscopic ultrasound (EUS) to count portal venous circulating tumor cells (CTCs), compared with paired peripheral CTCs, in patients with pancreaticobiliary cancers (PBCs). Full-Text PDF Open AccessIdentification of GLI Mutations in Patients With Hirschsprung Disease That Disrupt Enteric Nervous System Development in MiceGastroenterologyVol. 149Issue 7PreviewHirschsprung disease is characterized by a deficit in enteric neurons, which are derived from neural crest cells (NCCs). Aberrant hedgehog signaling disrupts NCC differentiation and might cause Hirschsprung disease. We performed genetic analyses to determine whether hedgehog signaling is involved in pathogenesis. Full-Text PDF Hirschsprung Disease and Activation of Hedgehog Signaling via GLI1-3 MutationsGastroenterologyVol. 149Issue 7PreviewHirschsprung disease (HSCR) is a congenital condition in which enteric neurons are missing from variable lengths of the distal bowel.1,2 Because the enteric nervous system (ENS) is essential for gut motility, affected infants suffer from functional obstruction and enterocolitis, and treatment requires surgery to remove the affected, aganglionic region. HSCR is a complex, polygenic disease, and mutations or variants in ≥15 genes have been associated with HSCR.3,4 Coding and noncoding mutations in the RET gene account for the majority of identified mutations associated with HSCR. Full-Text PDF Neutrophil Extracellular Traps Provide a Grip on the Enigmatic Pathogenesis of Acute PancreatitisGastroenterologyVol. 149Issue 7PreviewJames Hirsch reported in 1958 that histones can kill bacteria.1 He speculated that histones might be present in blood in the course of certain pathologic conditions, such as necrosis. The histones, which Hirsch used in his experiments, were extracted from neutrophils. Almost a half century later, Zychlinsky et al2 observed that neutrophils externalize granular proteins and nuclear components, including DNA and histones, in response to bacterial stimulation, which contribute to bacterial killing. Full-Text PDF