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Abstract

Increased Autoimmunity in Nonceliac Wheat Sensitivity Compared With Irritable Bowel SyndromeIn contrast with celiac disease, (CD) which is characterized by an immune-based reaction to gluten, primarily involving the small intestine, in genetically predisposed individuals, nonceliac gluten sensitivity or, more accurately, nonceliac wheat sensitivity (NCWS) is an emerging but less well-characterized clinical entity, although negative serum tissue transglutaminase and endomysial antibodies, absent intestinal villous atrophy, and negative immunoglobulin (Ig)E-mediated immune allergy tests to wheat are included as proposed criteria for the diagnosis. In this issue of Gastroenterology, Carroccio et al examine the prevalence of autoimmune disease and autoantibodies in NCWS. In the retrospective arm of the study composed of 131 patients with NCWS, diagnosed by double-blind placebo-controlled wheat challenge, 101 patients with CD, and 50 patients with irritable bowel syndrome (IBS), 46% of patients with NCWS had positive antinuclear antibodies (ANAs), with a median titer of 1:80, compared with 24% and 2% of patients with CD and IBS, respectively. In the prospective arm of the study composed of 42 patients with NCWS, 40 patients with CD, and 50 patients with IBS, patients with NCWS were also more likely to have positive ANAs (28% compared with 7.5% in patients with CD and 6% in patients with IBS). The presence of serum ANA in NCWS patients correlated with HLA DQ2/DQ8 haplotypes. In both arms of the study, patients with NCWS exhibited a frequency of autoimmune disorders similar to CD, in particular Hashimoto’s thyroiditis, and significantly higher than patient with IBS (Figure 1). These findings demonstrate a high prevalence of autoimmune disorders and ANA positivity, in association with HLA DQ2/DQ8 haplotypes, in patients with NCWS and may advance our understanding of NCWS as an evolving clinical entity.See page 596.Antiviral Treatment of Patients With HCV and Decompensated CirrhosisDramatic advances in the treatment of patients with chronic hepatitis C virus (HCV) infection have occurred with the development of all-oral direct-acting antiviral agents, including the NS5A inhibitor, ledipasvir, and the nucleotide polymerase inhibitor, sofosbuvir. However, few clinical trials have studied the response to treatment in patients with decompensated liver disease from chronic HCV infection, presently the most common indication for liver transplantation in North America and Europe. In this issue of Gastroenterology, Charlton et al report the results of an open-label phase 2 study (SOLAR-1), involving 29 clinical sites in the United States, to determine the efficacy and safety of a fixed-dose combination of ledipasvir-sofosbuvir with ribavirin for either 12 or 24 weeks in 337 patients with advanced liver disease owing to chronic HCV infection, including liver transplant recipients. All but 5 of the patients had HCV genotype 1 infection. Patients with cirrhosis who had not undergone liver transplantation were divided into groups with either moderate (Child–Pugh class B) or severe (Child-Pugh class C) hepatic impairment. Patients who had undergone liver transplantation were divided into groups without cirrhosis, with compensated cirrhosis and mild (Child–Pugh class A), moderate, and severe hepatic impairment, and patients with fibrosing cholestatic hepatitis. Rates of sustained virologic response (SVR) in patients with moderate hepatic impairment who had not undergone liver transplantation were 87% in those who received 12 weeks and 89% in those who received 24 weeks of treatment. Rates of SVR in patients with severe hepatic impairment who had not undergone liver transplantation were 86% in those who received 12 weeks and 87% in those who received 24 weeks of treatment. Rates of SVR in posttransplant patients with no or compensated cirrhosis ranged from 96% to 98%, regardless of the duration of treatment. Rates of SVR in posttransplant patients with moderate hepatic impairment were 86% in those who received 12 weeks and 88% in those who received 24 weeks of treatment. Rates of SVR in posttransplant patients with severe hepatic impairment were lower (60% in those who received 12 weeks and 75% in those who received 24 weeks of treatment), although there were only 9 patients in this group. All 6 patients with fibrosing cholestatic hepatitis achieved a SVR. SVR was associated with early improvements in Model for End-Stage Liver Disease scores (Figure 2). These findings demonstrate that ledipasvir-sofosbuvir plus ribavirin for 12 weeks is an effective treatment option in patients with advanced liver disease, including those with decompensated liver function before and after liver transplantation.Figure 2Change in Model for End-Stage Liver Disease score from baseline to follow-up week 12 in Child–Pugh class B and C patients.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See page 649.Role and Regulation of KIT Signaling in Colon Tumor Cell GrowthKIT, also known as CD117, is a receptor tyrosine kinase receptor that already has an established role in disease. Axel Ullrich first described KIT in 1987 as the cellular homolog of the feline sarcoma viral oncogene. In human disease, activating mutations in KIT were initially discovered in Philadelphia chromosome-positive chronic myelogenous leukemia and later in gastrointestinal stromal tumors. Rational drug design efforts focused on KIT resulted in the development of imatinib, which has provided dramatic therapeutic benefit for both chronic myelogenous leukemia and gastrointestinal stromal tumors.KIT expression was also characterized recently in gastrointestinal epithelial cells, where it is expressed by Paneth cells in the small intestine and CD24+ cells in the colon. These KIT+ cells support the intestinal stem cell, although its specific role remains unknown.In this issue of Gastroenterology, 2 groups—Fatrai et al from the University Medical Center Utrecht and the Academic Medical Centre in The Netherlands, and Chen et al from Stanford University—report on the impact of KIT expression in human colon cancers. Both groups established that KIT and its ligand (KITLG) potentiate the clonogenic potential of colonic tumors. Colonic tumors exhibit cellular heterogeneity with some cell populations expressing more differentiated features than the cancer stem cell. The authors established that the more differentiated KIT+ cells potentiated cancer stem cell growth, which promotes the overall propagation of colonic tumors. Disruption of either KIT or KITLG expression decreased the ability of the cancer cells to form clones in vitro or tumor xenografts in vivo. Both groups also found that KIT inhibited the expression of differentiated intestinal markers. Administration of imatinib to KIT+ colon cancer cells decreased the clonogenic capacity and decreased the size of xenografts in vivo (Figure 3).Figure 3Bioluminescence of colon cancer xenografts with and without imatinib treatment.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fatrai et al explored published gene expression profiles of several large colon cancer cohorts and found that cancers with high KIT or KITLG expression identified tumors with greater metastatic potential. Further analysis revealed a link between high KIT expression and genes that are induced by hypoxia. The authors established that hypoxia induces KIT expression and enhanced the clonogenic potential of cancer cells. The results have clinical implications because hypoxia is known to promote stem-like features that promote metastasis and tumor recurrence.An editorial by Yatrik Shah and Gijs van den Brink in this issue provides further insights into these 2 studies.See pages 692 and 705; editorial on page 534.Mechanism of Experimental Radiocontrast-Induced PancreatitisA troublesome outcome of endoscopic retrograde cholangiopancreatography (ERCP) is acute pancreatitis that is affects 1%-15% of cases. Suspected causative factors include the use of radiocontrast agents and increased hydrostatic pressure within the pancreatic duct. The specific mechanisms causing pancreatitis are unknown, but is explored in this issue of Gastroenterology by Jin et al. Using a murine model of pancreatic duct cannulation that simulates the ERCP procedure, the authors were able induce pancreatitis when radiocontrast was injected, which was not observed with normal saline. Independent variables for the induction of pancreatitis included the total volume injected into the duct and the radiocontrast concentration.Primary cultures of pancreatic acini were studied with confocal microscopy and fluorescent probes sensitive to intracellular calcium, and established that increased concentrations are present with the onset of pancreatitis. Elevated intracellular calcium is a known regulator of the inflammatory response by binding the Ca+2 -dependent phosphatase calcineurin, which activates nuclear factor of activated T cell (NFAT) and nuclear factor (NF)-κB to promote nuclear transcription of specific target genes. The authors discovered that calcineurin-binding inhibitors such as FK506 reduced the activation of NF-κB and NFAT, which also reduced pancreatitis-associated cell necrosis. When FK506 was administered during the murine model of ERCP-induced pancreatitis, the severity of the pancreatitis was decreased as measured by histology and serum amylase levels (Figure 4).Figure 4Amelioration of pancreatitis with FK506 in a murine model of endoscopic retrograde cholangiopancreatography-induced pancreatitis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)This study provided experimental evidence that elevated intracellular calcium is induced by the radiocontrast used in ERCP, which results in an inflammatory response that contributes to pancreatitis. The authors provide a potential therapeutic approach to reduce the severity and incidence of ERCP-associated pancreatitis.See page 753. Increased Autoimmunity in Nonceliac Wheat Sensitivity Compared With Irritable Bowel SyndromeIn contrast with celiac disease, (CD) which is characterized by an immune-based reaction to gluten, primarily involving the small intestine, in genetically predisposed individuals, nonceliac gluten sensitivity or, more accurately, nonceliac wheat sensitivity (NCWS) is an emerging but less well-characterized clinical entity, although negative serum tissue transglutaminase and endomysial antibodies, absent intestinal villous atrophy, and negative immunoglobulin (Ig)E-mediated immune allergy tests to wheat are included as proposed criteria for the diagnosis. In this issue of Gastroenterology, Carroccio et al examine the prevalence of autoimmune disease and autoantibodies in NCWS. In the retrospective arm of the study composed of 131 patients with NCWS, diagnosed by double-blind placebo-controlled wheat challenge, 101 patients with CD, and 50 patients with irritable bowel syndrome (IBS), 46% of patients with NCWS had positive antinuclear antibodies (ANAs), with a median titer of 1:80, compared with 24% and 2% of patients with CD and IBS, respectively. In the prospective arm of the study composed of 42 patients with NCWS, 40 patients with CD, and 50 patients with IBS, patients with NCWS were also more likely to have positive ANAs (28% compared with 7.5% in patients with CD and 6% in patients with IBS). The presence of serum ANA in NCWS patients correlated with HLA DQ2/DQ8 haplotypes. In both arms of the study, patients with NCWS exhibited a frequency of autoimmune disorders similar to CD, in particular Hashimoto’s thyroiditis, and significantly higher than patient with IBS (Figure 1). These findings demonstrate a high prevalence of autoimmune disorders and ANA positivity, in association with HLA DQ2/DQ8 haplotypes, in patients with NCWS and may advance our understanding of NCWS as an evolving clinical entity.See page 596. In contrast with celiac disease, (CD) which is characterized by an immune-based reaction to gluten, primarily involving the small intestine, in genetically predisposed individuals, nonceliac gluten sensitivity or, more accurately, nonceliac wheat sensitivity (NCWS) is an emerging but less well-characterized clinical entity, although negative serum tissue transglutaminase and endomysial antibodies, absent intestinal villous atrophy, and negative immunoglobulin (Ig)E-mediated immune allergy tests to wheat are included as proposed criteria for the diagnosis. In this issue of Gastroenterology, Carroccio et al examine the prevalence of autoimmune disease and autoantibodies in NCWS. In the retrospective arm of the study composed of 131 patients with NCWS, diagnosed by double-blind placebo-controlled wheat challenge, 101 patients with CD, and 50 patients with irritable bowel syndrome (IBS), 46% of patients with NCWS had positive antinuclear antibodies (ANAs), with a median titer of 1:80, compared with 24% and 2% of patients with CD and IBS, respectively. In the prospective arm of the study composed of 42 patients with NCWS, 40 patients with CD, and 50 patients with IBS, patients with NCWS were also more likely to have positive ANAs (28% compared with 7.5% in patients with CD and 6% in patients with IBS). The presence of serum ANA in NCWS patients correlated with HLA DQ2/DQ8 haplotypes. In both arms of the study, patients with NCWS exhibited a frequency of autoimmune disorders similar to CD, in particular Hashimoto’s thyroiditis, and significantly higher than patient with IBS (Figure 1). These findings demonstrate a high prevalence of autoimmune disorders and ANA positivity, in association with HLA DQ2/DQ8 haplotypes, in patients with NCWS and may advance our understanding of NCWS as an evolving clinical entity. See page 596. Antiviral Treatment of Patients With HCV and Decompensated CirrhosisDramatic advances in the treatment of patients with chronic hepatitis C virus (HCV) infection have occurred with the development of all-oral direct-acting antiviral agents, including the NS5A inhibitor, ledipasvir, and the nucleotide polymerase inhibitor, sofosbuvir. However, few clinical trials have studied the response to treatment in patients with decompensated liver disease from chronic HCV infection, presently the most common indication for liver transplantation in North America and Europe. In this issue of Gastroenterology, Charlton et al report the results of an open-label phase 2 study (SOLAR-1), involving 29 clinical sites in the United States, to determine the efficacy and safety of a fixed-dose combination of ledipasvir-sofosbuvir with ribavirin for either 12 or 24 weeks in 337 patients with advanced liver disease owing to chronic HCV infection, including liver transplant recipients. All but 5 of the patients had HCV genotype 1 infection. Patients with cirrhosis who had not undergone liver transplantation were divided into groups with either moderate (Child–Pugh class B) or severe (Child-Pugh class C) hepatic impairment. Patients who had undergone liver transplantation were divided into groups without cirrhosis, with compensated cirrhosis and mild (Child–Pugh class A), moderate, and severe hepatic impairment, and patients with fibrosing cholestatic hepatitis. Rates of sustained virologic response (SVR) in patients with moderate hepatic impairment who had not undergone liver transplantation were 87% in those who received 12 weeks and 89% in those who received 24 weeks of treatment. Rates of SVR in patients with severe hepatic impairment who had not undergone liver transplantation were 86% in those who received 12 weeks and 87% in those who received 24 weeks of treatment. Rates of SVR in posttransplant patients with no or compensated cirrhosis ranged from 96% to 98%, regardless of the duration of treatment. Rates of SVR in posttransplant patients with moderate hepatic impairment were 86% in those who received 12 weeks and 88% in those who received 24 weeks of treatment. Rates of SVR in posttransplant patients with severe hepatic impairment were lower (60% in those who received 12 weeks and 75% in those who received 24 weeks of treatment), although there were only 9 patients in this group. All 6 patients with fibrosing cholestatic hepatitis achieved a SVR. SVR was associated with early improvements in Model for End-Stage Liver Disease scores (Figure 2). These findings demonstrate that ledipasvir-sofosbuvir plus ribavirin for 12 weeks is an effective treatment option in patients with advanced liver disease, including those with decompensated liver function before and after liver transplantation.See page 649. Dramatic advances in the treatment of patients with chronic hepatitis C virus (HCV) infection have occurred with the development of all-oral direct-acting antiviral agents, including the NS5A inhibitor, ledipasvir, and the nucleotide polymerase inhibitor, sofosbuvir. However, few clinical trials have studied the response to treatment in patients with decompensated liver disease from chronic HCV infection, presently the most common indication for liver transplantation in North America and Europe. In this issue of Gastroenterology, Charlton et al report the results of an open-label phase 2 study (SOLAR-1), involving 29 clinical sites in the United States, to determine the efficacy and safety of a fixed-dose combination of ledipasvir-sofosbuvir with ribavirin for either 12 or 24 weeks in 337 patients with advanced liver disease owing to chronic HCV infection, including liver transplant recipients. All but 5 of the patients had HCV genotype 1 infection. Patients with cirrhosis who had not undergone liver transplantation were divided into groups with either moderate (Child–Pugh class B) or severe (Child-Pugh class C) hepatic impairment. Patients who had undergone liver transplantation were divided into groups without cirrhosis, with compensated cirrhosis and mild (Child–Pugh class A), moderate, and severe hepatic impairment, and patients with fibrosing cholestatic hepatitis. Rates of sustained virologic response (SVR) in patients with moderate hepatic impairment who had not undergone liver transplantation were 87% in those who received 12 weeks and 89% in those who received 24 weeks of treatment. Rates of SVR in patients with severe hepatic impairment who had not undergone liver transplantation were 86% in those who received 12 weeks and 87% in those who received 24 weeks of treatment. Rates of SVR in posttransplant patients with no or compensated cirrhosis ranged from 96% to 98%, regardless of the duration of treatment. Rates of SVR in posttransplant patients with moderate hepatic impairment were 86% in those who received 12 weeks and 88% in those who received 24 weeks of treatment. Rates of SVR in posttransplant patients with severe hepatic impairment were lower (60% in those who received 12 weeks and 75% in those who received 24 weeks of treatment), although there were only 9 patients in this group. All 6 patients with fibrosing cholestatic hepatitis achieved a SVR. SVR was associated with early improvements in Model for End-Stage Liver Disease scores (Figure 2). These findings demonstrate that ledipasvir-sofosbuvir plus ribavirin for 12 weeks is an effective treatment option in patients with advanced liver disease, including those with decompensated liver function before and after liver transplantation. See page 649. Role and Regulation of KIT Signaling in Colon Tumor Cell GrowthKIT, also known as CD117, is a receptor tyrosine kinase receptor that already has an established role in disease. Axel Ullrich first described KIT in 1987 as the cellular homolog of the feline sarcoma viral oncogene. In human disease, activating mutations in KIT were initially discovered in Philadelphia chromosome-positive chronic myelogenous leukemia and later in gastrointestinal stromal tumors. Rational drug design efforts focused on KIT resulted in the development of imatinib, which has provided dramatic therapeutic benefit for both chronic myelogenous leukemia and gastrointestinal stromal tumors.KIT expression was also characterized recently in gastrointestinal epithelial cells, where it is expressed by Paneth cells in the small intestine and CD24+ cells in the colon. These KIT+ cells support the intestinal stem cell, although its specific role remains unknown.In this issue of Gastroenterology, 2 groups—Fatrai et al from the University Medical Center Utrecht and the Academic Medical Centre in The Netherlands, and Chen et al from Stanford University—report on the impact of KIT expression in human colon cancers. Both groups established that KIT and its ligand (KITLG) potentiate the clonogenic potential of colonic tumors. Colonic tumors exhibit cellular heterogeneity with some cell populations expressing more differentiated features than the cancer stem cell. The authors established that the more differentiated KIT+ cells potentiated cancer stem cell growth, which promotes the overall propagation of colonic tumors. Disruption of either KIT or KITLG expression decreased the ability of the cancer cells to form clones in vitro or tumor xenografts in vivo. Both groups also found that KIT inhibited the expression of differentiated intestinal markers. Administration of imatinib to KIT+ colon cancer cells decreased the clonogenic capacity and decreased the size of xenografts in vivo (Figure 3).Fatrai et al explored published gene expression profiles of several large colon cancer cohorts and found that cancers with high KIT or KITLG expression identified tumors with greater metastatic potential. Further analysis revealed a link between high KIT expression and genes that are induced by hypoxia. The authors established that hypoxia induces KIT expression and enhanced the clonogenic potential of cancer cells. The results have clinical implications because hypoxia is known to promote stem-like features that promote metastasis and tumor recurrence.An editorial by Yatrik Shah and Gijs van den Brink in this issue provides further insights into these 2 studies.See pages 692 and 705; editorial on page 534. KIT, also known as CD117, is a receptor tyrosine kinase receptor that already has an established role in disease. Axel Ullrich first described KIT in 1987 as the cellular homolog of the feline sarcoma viral oncogene. In human disease, activating mutations in KIT were initially discovered in Philadelphia chromosome-positive chronic myelogenous leukemia and later in gastrointestinal stromal tumors. Rational drug design efforts focused on KIT resulted in the development of imatinib, which has provided dramatic therapeutic benefit for both chronic myelogenous leukemia and gastrointestinal stromal tumors. KIT expression was also characterized recently in gastrointestinal epithelial cells, where it is expressed by Paneth cells in the small intestine and CD24+ cells in the colon. These KIT+ cells support the intestinal stem cell, although its specific role remains unknown. In this issue of Gastroenterology, 2 groups—Fatrai et al from the University Medical Center Utrecht and the Academic Medical Centre in The Netherlands, and Chen et al from Stanford University—report on the impact of KIT expression in human colon cancers. Both groups established that KIT and its ligand (KITLG) potentiate the clonogenic potential of colonic tumors. Colonic tumors exhibit cellular heterogeneity with some cell populations expressing more differentiated features than the cancer stem cell. The authors established that the more differentiated KIT+ cells potentiated cancer stem cell growth, which promotes the overall propagation of colonic tumors. Disruption of either KIT or KITLG expression decreased the ability of the cancer cells to form clones in vitro or tumor xenografts in vivo. Both groups also found that KIT inhibited the expression of differentiated intestinal markers. Administration of imatinib to KIT+ colon cancer cells decreased the clonogenic capacity and decreased the size of xenografts in vivo (Figure 3). Fatrai et al explored published gene expression profiles of several large colon cancer cohorts and found that cancers with high KIT or KITLG expression identified tumors with greater metastatic potential. Further analysis revealed a link between high KIT expression and genes that are induced by hypoxia. The authors established that hypoxia induces KIT expression and enhanced the clonogenic potential of cancer cells. The results have clinical implications because hypoxia is known to promote stem-like features that promote metastasis and tumor recurrence. An editorial by Yatrik Shah and Gijs van den Brink in this issue provides further insights into these 2 studies. See pages 692 and 705; editorial on page 534. Mechanism of Experimental Radiocontrast-Induced PancreatitisA troublesome outcome of endoscopic retrograde cholangiopancreatography (ERCP) is acute pancreatitis that is affects 1%-15% of cases. Suspected causative factors include the use of radiocontrast agents and increased hydrostatic pressure within the pancreatic duct. The specific mechanisms causing pancreatitis are unknown, but is explored in this issue of Gastroenterology by Jin et al. Using a murine model of pancreatic duct cannulation that simulates the ERCP procedure, the authors were able induce pancreatitis when radiocontrast was injected, which was not observed with normal saline. Independent variables for the induction of pancreatitis included the total volume injected into the duct and the radiocontrast concentration.Primary cultures of pancreatic acini were studied with confocal microscopy and fluorescent probes sensitive to intracellular calcium, and established that increased concentrations are present with the onset of pancreatitis. Elevated intracellular calcium is a known regulator of the inflammatory response by binding the Ca+2 -dependent phosphatase calcineurin, which activates nuclear factor of activated T cell (NFAT) and nuclear factor (NF)-κB to promote nuclear transcription of specific target genes. The authors discovered that calcineurin-binding inhibitors such as FK506 reduced the activation of NF-κB and NFAT, which also reduced pancreatitis-associated cell necrosis. When FK506 was administered during the murine model of ERCP-induced pancreatitis, the severity of the pancreatitis was decreased as measured by histology and serum amylase levels (Figure 4).This study provided experimental evidence that elevated intracellular calcium is induced by the radiocontrast used in ERCP, which results in an inflammatory response that contributes to pancreatitis. The authors provide a potential therapeutic approach to reduce the severity and incidence of ERCP-associated pancreatitis.See page 753. A troublesome outcome of endoscopic retrograde cholangiopancreatography (ERCP) is acute pancreatitis that is affects 1%-15% of cases. Suspected causative factors include the use of radiocontrast agents and increased hydrostatic pressure within the pancreatic duct. The specific mechanisms causing pancreatitis are unknown, but is explored in this issue of Gastroenterology by Jin et al. Using a murine model of pancreatic duct cannulation that simulates the ERCP procedure, the authors were able induce pancreatitis when radiocontrast was injected, which was not observed with normal saline. Independent variables for the induction of pancreatitis included the total volume injected into the duct and the radiocontrast concentration. Primary cultures of pancreatic acini were studied with confocal microscopy and fluorescent probes sensitive to intracellular calcium, and established that increased concentrations are present with the onset of pancreatitis. Elevated intracellular calcium is a known regulator of the inflammatory response by binding the Ca+2 -dependent phosphatase calcineurin, which activates nuclear factor of activated T cell (NFAT) and nuclear factor (NF)-κB to promote nuclear transcription of specific target genes. The authors discovered that calcineurin-binding inhibitors such as FK506 reduced the activation of NF-κB and NFAT, which also reduced pancreatitis-associated cell necrosis. When FK506 was administered during the murine model of ERCP-induced pancreatitis, the severity of the pancreatitis was decreased as measured by histology and serum amylase levels (Figure 4). This study provided experimental evidence that elevated intracellular calcium is induced by the radiocontrast used in ERCP, which results in an inflammatory response that contributes to pancreatitis. The authors provide a potential therapeutic approach to reduce the severity and incidence of ERCP-associated pancreatitis. See page 753. High Proportions of People With Nonceliac Wheat Sensitivity Have Autoimmune Disease or Antinuclear AntibodiesGastroenterologyVol. 149Issue 3PreviewThere is much interest in wheat sensitivity among people without celiac disease (CD), but little is known about any risks associated with the condition. We evaluated the prevalence of autoimmune diseases (ADs) among patients with nonceliac wheat sensitivity (NCWS), and investigated whether they carry antinuclear antibodies (ANA). Full-Text PDF Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver DiseaseGastroenterologyVol. 149Issue 3PreviewThere are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Full-Text PDF Open AccessMaintenance of Clonogenic KIT+ Human Colon Tumor Cells Requires Secretion of Stem Cell Factor by Differentiated Tumor CellsGastroenterologyVol. 149Issue 3PreviewColon tumors contain a fraction of undifferentiated stem cell−like cancer cells with high tumorigenic potential. Little is known about the signals that maintain these stem-like cells. We investigated whether differentiated tumor cells provide support. Full-Text PDF Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and CalcineurinGastroenterologyVol. 149Issue 3PreviewRadiocontrast agents are required for radiographic procedures, but these agents can injure tissues by unknown mechanisms. We investigated whether exposure of pancreatic tissues to radiocontrast agents during endoscopic retrograde cholangiopancreatography (ERCP) causes pancreatic inflammation, and studied the effects of these agents on human cell lines and in mice. Full-Text PDF c-Kit as a Novel Potential Therapeutic Target in Colorectal CancerGastroenterologyVol. 149Issue 3PreviewStudies to identify the cells that fuel colorectal cancer (CRC) cell renewal and metastasis have shown that such behavior is enriched in a subpopulation of cells with stem cell-like features or tumor-initiating cells. The identification of drugs that target tumor-initiating cells in CRC will provide unique, new therapeutic opportunities. Two publications in this issue of Gastroenterology now demonstrate an important role for c-Kit signaling, a receptor tyrosine kinase that can be targeted with the clinically approved inhibitor imatinib, in the growth and maintenance of tumor-initiating cells in CRC. Full-Text PDF KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon CancersGastroenterologyVol. 149Issue 3PreviewReceptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. We investigated the role of the RTK KIT in development of human colon cancer. Full-Text PDF