This Month in Gastroenterology

Abstract

Discovery and Identification of α-Defensins as Low-Abundant, Tumor-Derived, Serum Markers in Colorectal CancerOver the last several years there have been great advances in genomic and proteomic techniques providing great opportunities to identify relevant biomarkers that could improve our diagnosis and treatment of cancer. Specific gene mutations and epigenetic changes involved in the progression of colon adenomas to colon cancer have been well studied. Despite our advances in understanding mechanisms involved in tumor development, there have been few studies identifying relevant serum markers for colon cancer. In this issue, Melle et al describe their strategy for identifying reliable biomarkers for cancer diagnosis. The authors analyzed protein expression profiles of 39 colon tumor samples and adjacent normal mucosa using ProteinChip Arrays (Figure 1). Using these arrays, protein expression profiles were analyzed and revealed 3 differentially expressed peaks of α-defensins 1-3 (HNP 1-3). Immunohistochemical analysis was subsequently performed on the tissue samples confirming the up-regulation of these proteins in the tumor tissue (Figure 2). Positive tissues were reanalyzed with the ProteinChip arrays and demonstrated that these proteins were HNP 1-3. Serum samples were also collected from patients with colon cancer (n = 48) and normal controls (n = 42). ELISA analysis was performed to quantify HNP1-3. The median HNP1-3 concentration was 8.1 ng/mL in normal controls compared with 29.4 ng/mL in patients with colon cancer (P = 2.14 × 10−5). Receiver operating characteristic curves determined an average sensitivity and specificity for the detection of colorectal cancer through serum measurement of HNP 1–3 of 100% and 69%, respectively.Figure 2Immunohistochemistry (IHC) of HNP1-3 visualized by normal and laser scanning microscopy (LSM; positive reaction is depicted in blue). (A and B) IHC of HNP1-3 on colon carcinoma. (A) Increased signal intensity in carcinoma (Ca) structures (overview with 25× magnification; N, normal epithelium). (B) Strong positive reaction of invasive growing carcinoma complexes (Ca; magnification of 120×).View Large Image Figure ViewerDownload (PPT)Biomarkers measured in serum are ideal for screening high-risk individuals for cancer although the identification of reliable and significant markers is a difficult task. These authors have described a systematic approach to identify such serum biomarkers. It appears α-defensins 1-3 may be promising biomarkers for colon cancer.NAFLD Increases Risk of Death Compared With General PopulationThe prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in the United States. Previous studies determining the natural history of NAFLD have been performed at tertiary care centers and therefore likely reflect the natural history of patients with more severe disease. There have been no studies to date examining the long-term prognosis of NAFLD in the general population. Adams et al now report the results of their population-based cohort study determining survival and liver-related morbidity and mortality among community-based NAFLD patients in comparison with the Minnesota general population of same age and gender. These authors studied 420 patients diagnosed with NAFLD, confirmed on imaging studies or liver biopsy, in Olmsted County, Minnesota, between 1980 and 2000 (Figure 3). Medical records were reviewed to determine outcomes up to 2003. The results show that mortality was significantly higher in community-based NAFLD patients compared with the expected mortality of the general Minnesota population. Death in this cohort was associated with older age, cirrhosis, and impaired fasting glycemia. It appears the potential burden of NAFLD in the community setting is of considerable concern given the high prevalence of this disease.Figure 3Overall survival of patients diagnosed with NAFLD in Olmsted County, Minnesota, between January 1, 1980 and January 1, 2000. Survival is compared with the general population of Minnesota of the same age and sex.View Large Image Figure ViewerDownload (PPT)L-glutamine Anti-Apoptotic Effects Mediated by Heat Shock ProteinsL- glutamine (L-gln) is the most abundant amino acid in the plasma and is synthesized and stored in several tissues. However, during severe stress, L-gln becomes conditionally essential because levels can decrease by more than 50% and plasma concentrations by 30%. In the intestine, L-gln has trophic effects which when blocked by inhibition of glutaminase, diarrhea and mucosal ulceration result. L-gln supplementation protects intestinal mucosa integrity during severe physiological stress in states of sepsis, burns, hypoxia-reperfusion-induced mucosal injury, and radiation-induced enterocolitis, effects that may be mediated through the modulation of cytoprotective heat shock proteins. Systemic infusions of L-gln in the rat, for instance, have been shown to up-regulate stress-induced Hsp72 expression in several tissues including the intestine.Heat shock proteins (Hsp) are a highly conserved family of molecular chaperones, some or which are rapidly induced by various physiological stresses through incompletely understood mechanisms that involve preferential transcription and translation. The article by Ropeleski et al shows that L-gln is essential for the induction of the Hsp response, ie, without it, the induction of Hsp is markedly attenuated. Using the nontransformed rat IEC-18 intestinal crypt-like cell line and the human H4 embryonic intestinal epithelial cell line, the investigators demonstrate that the withdrawal of L-gln specifically augments Hsp72 transcript abundance and HSF-1 DNA transcription factor binding during heat shock, an effect that did not involve changes in HSF-1 phosphorylation, trimerization, nuclear localization during heat shock, or HSF-1 minimal promoter activity. Nevertheless, the presence of L-glutamine was essential for Hsp72 promoter transcriptional activation. The functional consequence of depleted L-gln was demonstrated by increased camptothecin-induced caspase-3 and PARP cleavage in glutamine-deficient cells (Figure 4). Taken together, the data suggest that glutamine potentiation of the Hsp72 response is mediated through modulation of HSF-1 DNA binding and Hsp72 promoter activation. Glutamine depletion during stress conditions would therefore decrease epithelial resistance to apoptotic injury.Figure 4L-glutamine potentiation of Hsp72 induction by L-glutamine is associated with decreased caspase 3 activation. Two hours after heat shock, cells were exposed to 20 μmol/L camptothecin, a topoisomerase II inhibitor. The glutamine effect on Hsp72 was associated with the delayed appearance and decreased abundance of (A) cleaved caspase-3 (17-19 kilodalton) and (B) large and small cleaved fragments of PARP.View Large Image Figure ViewerDownload (PPT)Growth Hormone Reduces Inflammation, Promotes Mucosal Healing, and Decreases Inflammation-Induced FibrosisIn this issue, there are studies by Han et al and Theiss et al that explore the actions of growth hormone in the context of intestinal inflammatory disease. Growth hormone (GH) has been used to treat patients with Crohn’s disease (CD), although clinical trials have been limited. In experimental models of intestinal inflammation induced by dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS) administration, GH has been shown to reduce mucosal inflammation and accelerate epithelial healing. Because the underlying mechanisms mediating these actions were unknown, Han et al examined the possibility that GH administration reduces disease activity in experimental colitis by modulating SHP2:gp130 association and inhibiting STAT3 activation. STAT3 is constitutively activated in human and experimental colitis, resulting in activated lamina propria T cells resistant to apoptosis and proliferation colonic epithelial crypt cells. Part of the STAT3 activation process may be dependent on stimulation of gp130 signaling receptors by agents like IL-6. However, SHP-2 and suppressor of cytokine signaling 3 (SOCS-3) are negative regulators of gp130 and inhibit STAT3 activation.The study by Han et al demonstrated that GH administration is associated with weight gain and improvement in colon histology in IL-10 null mice with colitis (Figure 5). GH also inhibited apoptosis and increased proliferation of crypt epithelial cells, while increasing apoptosis of lamina propria mononuclear cells – effects that were associated with SHP2:gp130 association and reduced colonic STAT3 activation. Similar findings were noted in colonic specimens from patients with Crohn’s disease.Figure 5GH administration improves colon disease activity. (A) GHR expressing cells were identified in PBS treated WT and IL-10 null mice by IHC using the AL-47 GHR antibody. (A) WT, (B) IL-10 null, and (C) negative control. Representative positive CEC and LPMC are identified with the closed arrows.View Large Image Figure ViewerDownload (PPT)In the study by Theiss et al, the effects of GH treatment on mucosal inflammation and fibrosis were studied in an animal model of chronic, experimental granulomatous enterocolitis. One of the potential complications of GH treatment is exacerbation of intestinal fibrosis, which is a frequent development in patients with Crohn’s disease leading to stricture and fistula formation. Peptidoglycan-polysaccharide (PG-APS) or control human serum albumin (HSA) was injected into the cecum and ileum of rats to induce chronic enterocolitis. At the onset of reactivation of chronic inflammation in PG-APS groups, recombinant human GH or vehicle were administered for 14 days. In PG-APS-injected rats, GH improved a number of inflammatory complications, including reduced joint diameter, grossly detected adhesions, and mesenteric contractions, cecal fibrosis score, and collagen expression (Figure 6). This was associated with increased SOCS-3 mRNA and protein abundance in areas of increased collagen deposition. However, no effects on intestinal inflammation were observed.Figure 6Bright-field photomicrographs of representative cecum sections stained with Sirius red for collagen. HSA control rats treated with vehicle or GH had low fibrosis scores (< 1.0) with the majority of collagen deposition located within the submucosa, as is found in the normal cecum (A and B). PG-APS rats showed obvious increases in transmural collagen deposition (C–F), validated by significant increases in mean histological scores for fibrosis. PG-APS rats treated with GH had a modest, but significant, reduction in histological scores for fibrosis compared with PG-APS-injected rats given vehicle, as illustrated also by the representative sections in C and E versus D and F.View Large Image Figure ViewerDownload (PPT)Both studies provide important insights into the mechanisms of GH action in mitigating the effects of intestinal inflammation. Moreover, GH does not appear to exacerbate fibrosis, but rather has anti-fibrogenic actions mediated by the induction of SOCS-3 expression. Collectively, these data provide promise and rational for GH as a novel mechanism of treating patients with IBD. Discovery and Identification of α-Defensins as Low-Abundant, Tumor-Derived, Serum Markers in Colorectal CancerOver the last several years there have been great advances in genomic and proteomic techniques providing great opportunities to identify relevant biomarkers that could improve our diagnosis and treatment of cancer. Specific gene mutations and epigenetic changes involved in the progression of colon adenomas to colon cancer have been well studied. Despite our advances in understanding mechanisms involved in tumor development, there have been few studies identifying relevant serum markers for colon cancer. In this issue, Melle et al describe their strategy for identifying reliable biomarkers for cancer diagnosis. The authors analyzed protein expression profiles of 39 colon tumor samples and adjacent normal mucosa using ProteinChip Arrays (Figure 1). Using these arrays, protein expression profiles were analyzed and revealed 3 differentially expressed peaks of α-defensins 1-3 (HNP 1-3). Immunohistochemical analysis was subsequently performed on the tissue samples confirming the up-regulation of these proteins in the tumor tissue (Figure 2). Positive tissues were reanalyzed with the ProteinChip arrays and demonstrated that these proteins were HNP 1-3. Serum samples were also collected from patients with colon cancer (n = 48) and normal controls (n = 42). ELISA analysis was performed to quantify HNP1-3. The median HNP1-3 concentration was 8.1 ng/mL in normal controls compared with 29.4 ng/mL in patients with colon cancer (P = 2.14 × 10−5). Receiver operating characteristic curves determined an average sensitivity and specificity for the detection of colorectal cancer through serum measurement of HNP 1–3 of 100% and 69%, respectively.Biomarkers measured in serum are ideal for screening high-risk individuals for cancer although the identification of reliable and significant markers is a difficult task. These authors have described a systematic approach to identify such serum biomarkers. It appears α-defensins 1-3 may be promising biomarkers for colon cancer. Over the last several years there have been great advances in genomic and proteomic techniques providing great opportunities to identify relevant biomarkers that could improve our diagnosis and treatment of cancer. Specific gene mutations and epigenetic changes involved in the progression of colon adenomas to colon cancer have been well studied. Despite our advances in understanding mechanisms involved in tumor development, there have been few studies identifying relevant serum markers for colon cancer. In this issue, Melle et al describe their strategy for identifying reliable biomarkers for cancer diagnosis. The authors analyzed protein expression profiles of 39 colon tumor samples and adjacent normal mucosa using ProteinChip Arrays (Figure 1). Using these arrays, protein expression profiles were analyzed and revealed 3 differentially expressed peaks of α-defensins 1-3 (HNP 1-3). Immunohistochemical analysis was subsequently performed on the tissue samples confirming the up-regulation of these proteins in the tumor tissue (Figure 2). Positive tissues were reanalyzed with the ProteinChip arrays and demonstrated that these proteins were HNP 1-3. Serum samples were also collected from patients with colon cancer (n = 48) and normal controls (n = 42). ELISA analysis was performed to quantify HNP1-3. The median HNP1-3 concentration was 8.1 ng/mL in normal controls compared with 29.4 ng/mL in patients with colon cancer (P = 2.14 × 10−5). Receiver operating characteristic curves determined an average sensitivity and specificity for the detection of colorectal cancer through serum measurement of HNP 1–3 of 100% and 69%, respectively. Biomarkers measured in serum are ideal for screening high-risk individuals for cancer although the identification of reliable and significant markers is a difficult task. These authors have described a systematic approach to identify such serum biomarkers. It appears α-defensins 1-3 may be promising biomarkers for colon cancer. NAFLD Increases Risk of Death Compared With General PopulationThe prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in the United States. Previous studies determining the natural history of NAFLD have been performed at tertiary care centers and therefore likely reflect the natural history of patients with more severe disease. There have been no studies to date examining the long-term prognosis of NAFLD in the general population. Adams et al now report the results of their population-based cohort study determining survival and liver-related morbidity and mortality among community-based NAFLD patients in comparison with the Minnesota general population of same age and gender. These authors studied 420 patients diagnosed with NAFLD, confirmed on imaging studies or liver biopsy, in Olmsted County, Minnesota, between 1980 and 2000 (Figure 3). Medical records were reviewed to determine outcomes up to 2003. The results show that mortality was significantly higher in community-based NAFLD patients compared with the expected mortality of the general Minnesota population. Death in this cohort was associated with older age, cirrhosis, and impaired fasting glycemia. It appears the potential burden of NAFLD in the community setting is of considerable concern given the high prevalence of this disease. The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in the United States. Previous studies determining the natural history of NAFLD have been performed at tertiary care centers and therefore likely reflect the natural history of patients with more severe disease. There have been no studies to date examining the long-term prognosis of NAFLD in the general population. Adams et al now report the results of their population-based cohort study determining survival and liver-related morbidity and mortality among community-based NAFLD patients in comparison with the Minnesota general population of same age and gender. These authors studied 420 patients diagnosed with NAFLD, confirmed on imaging studies or liver biopsy, in Olmsted County, Minnesota, between 1980 and 2000 (Figure 3). Medical records were reviewed to determine outcomes up to 2003. The results show that mortality was significantly higher in community-based NAFLD patients compared with the expected mortality of the general Minnesota population. Death in this cohort was associated with older age, cirrhosis, and impaired fasting glycemia. It appears the potential burden of NAFLD in the community setting is of considerable concern given the high prevalence of this disease. L-glutamine Anti-Apoptotic Effects Mediated by Heat Shock ProteinsL- glutamine (L-gln) is the most abundant amino acid in the plasma and is synthesized and stored in several tissues. However, during severe stress, L-gln becomes conditionally essential because levels can decrease by more than 50% and plasma concentrations by 30%. In the intestine, L-gln has trophic effects which when blocked by inhibition of glutaminase, diarrhea and mucosal ulceration result. L-gln supplementation protects intestinal mucosa integrity during severe physiological stress in states of sepsis, burns, hypoxia-reperfusion-induced mucosal injury, and radiation-induced enterocolitis, effects that may be mediated through the modulation of cytoprotective heat shock proteins. Systemic infusions of L-gln in the rat, for instance, have been shown to up-regulate stress-induced Hsp72 expression in several tissues including the intestine.Heat shock proteins (Hsp) are a highly conserved family of molecular chaperones, some or which are rapidly induced by various physiological stresses through incompletely understood mechanisms that involve preferential transcription and translation. The article by Ropeleski et al shows that L-gln is essential for the induction of the Hsp response, ie, without it, the induction of Hsp is markedly attenuated. Using the nontransformed rat IEC-18 intestinal crypt-like cell line and the human H4 embryonic intestinal epithelial cell line, the investigators demonstrate that the withdrawal of L-gln specifically augments Hsp72 transcript abundance and HSF-1 DNA transcription factor binding during heat shock, an effect that did not involve changes in HSF-1 phosphorylation, trimerization, nuclear localization during heat shock, or HSF-1 minimal promoter activity. Nevertheless, the presence of L-glutamine was essential for Hsp72 promoter transcriptional activation. The functional consequence of depleted L-gln was demonstrated by increased camptothecin-induced caspase-3 and PARP cleavage in glutamine-deficient cells (Figure 4). Taken together, the data suggest that glutamine potentiation of the Hsp72 response is mediated through modulation of HSF-1 DNA binding and Hsp72 promoter activation. Glutamine depletion during stress conditions would therefore decrease epithelial resistance to apoptotic injury. L- glutamine (L-gln) is the most abundant amino acid in the plasma and is synthesized and stored in several tissues. However, during severe stress, L-gln becomes conditionally essential because levels can decrease by more than 50% and plasma concentrations by 30%. In the intestine, L-gln has trophic effects which when blocked by inhibition of glutaminase, diarrhea and mucosal ulceration result. L-gln supplementation protects intestinal mucosa integrity during severe physiological stress in states of sepsis, burns, hypoxia-reperfusion-induced mucosal injury, and radiation-induced enterocolitis, effects that may be mediated through the modulation of cytoprotective heat shock proteins. Systemic infusions of L-gln in the rat, for instance, have been shown to up-regulate stress-induced Hsp72 expression in several tissues including the intestine. Heat shock proteins (Hsp) are a highly conserved family of molecular chaperones, some or which are rapidly induced by various physiological stresses through incompletely understood mechanisms that involve preferential transcription and translation. The article by Ropeleski et al shows that L-gln is essential for the induction of the Hsp response, ie, without it, the induction of Hsp is markedly attenuated. Using the nontransformed rat IEC-18 intestinal crypt-like cell line and the human H4 embryonic intestinal epithelial cell line, the investigators demonstrate that the withdrawal of L-gln specifically augments Hsp72 transcript abundance and HSF-1 DNA transcription factor binding during heat shock, an effect that did not involve changes in HSF-1 phosphorylation, trimerization, nuclear localization during heat shock, or HSF-1 minimal promoter activity. Nevertheless, the presence of L-glutamine was essential for Hsp72 promoter transcriptional activation. The functional consequence of depleted L-gln was demonstrated by increased camptothecin-induced caspase-3 and PARP cleavage in glutamine-deficient cells (Figure 4). Taken together, the data suggest that glutamine potentiation of the Hsp72 response is mediated through modulation of HSF-1 DNA binding and Hsp72 promoter activation. Glutamine depletion during stress conditions would therefore decrease epithelial resistance to apoptotic injury. Growth Hormone Reduces Inflammation, Promotes Mucosal Healing, and Decreases Inflammation-Induced FibrosisIn this issue, there are studies by Han et al and Theiss et al that explore the actions of growth hormone in the context of intestinal inflammatory disease. Growth hormone (GH) has been used to treat patients with Crohn’s disease (CD), although clinical trials have been limited. In experimental models of intestinal inflammation induced by dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS) administration, GH has been shown to reduce mucosal inflammation and accelerate epithelial healing. Because the underlying mechanisms mediating these actions were unknown, Han et al examined the possibility that GH administration reduces disease activity in experimental colitis by modulating SHP2:gp130 association and inhibiting STAT3 activation. STAT3 is constitutively activated in human and experimental colitis, resulting in activated lamina propria T cells resistant to apoptosis and proliferation colonic epithelial crypt cells. Part of the STAT3 activation process may be dependent on stimulation of gp130 signaling receptors by agents like IL-6. However, SHP-2 and suppressor of cytokine signaling 3 (SOCS-3) are negative regulators of gp130 and inhibit STAT3 activation.The study by Han et al demonstrated that GH administration is associated with weight gain and improvement in colon histology in IL-10 null mice with colitis (Figure 5). GH also inhibited apoptosis and increased proliferation of crypt epithelial cells, while increasing apoptosis of lamina propria mononuclear cells – effects that were associated with SHP2:gp130 association and reduced colonic STAT3 activation. Similar findings were noted in colonic specimens from patients with Crohn’s disease.In the study by Theiss et al, the effects of GH treatment on mucosal inflammation and fibrosis were studied in an animal model of chronic, experimental granulomatous enterocolitis. One of the potential complications of GH treatment is exacerbation of intestinal fibrosis, which is a frequent development in patients with Crohn’s disease leading to stricture and fistula formation. Peptidoglycan-polysaccharide (PG-APS) or control human serum albumin (HSA) was injected into the cecum and ileum of rats to induce chronic enterocolitis. At the onset of reactivation of chronic inflammation in PG-APS groups, recombinant human GH or vehicle were administered for 14 days. In PG-APS-injected rats, GH improved a number of inflammatory complications, including reduced joint diameter, grossly detected adhesions, and mesenteric contractions, cecal fibrosis score, and collagen expression (Figure 6). This was associated with increased SOCS-3 mRNA and protein abundance in areas of increased collagen deposition. However, no effects on intestinal inflammation were observed.Figure 6Bright-field photomicrographs of representative cecum sections stained with Sirius red for collagen. HSA control rats treated with vehicle or GH had low fibrosis scores (< 1.0) with the majority of collagen deposition located within the submucosa, as is found in the normal cecum (A and B). PG-APS rats showed obvious increases in transmural collagen deposition (C–F), validated by significant increases in mean histological scores for fibrosis. PG-APS rats treated with GH had a modest, but significant, reduction in histological scores for fibrosis compared with PG-APS-injected rats given vehicle, as illustrated also by the representative sections in C and E versus D and F.View Large Image Figure ViewerDownload (PPT)Both studies provide important insights into the mechanisms of GH action in mitigating the effects of intestinal inflammation. Moreover, GH does not appear to exacerbate fibrosis, but rather has anti-fibrogenic actions mediated by the induction of SOCS-3 expression. Collectively, these data provide promise and rational for GH as a novel mechanism of treating patients with IBD. In this issue, there are studies by Han et al and Theiss et al that explore the actions of growth hormone in the context of intestinal inflammatory disease. Growth hormone (GH) has been used to treat patients with Crohn’s disease (CD), although clinical trials have been limited. In experimental models of intestinal inflammation induced by dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS) administration, GH has been shown to reduce mucosal inflammation and accelerate epithelial healing. Because the underlying mechanisms mediating these actions were unknown, Han et al examined the possibility that GH administration reduces disease activity in experimental colitis by modulating SHP2:gp130 association and inhibiting STAT3 activation. STAT3 is constitutively activated in human and experimental colitis, resulting in activated lamina propria T cells resistant to apoptosis and proliferation colonic epithelial crypt cells. Part of the STAT3 activation process may be dependent on stimulation of gp130 signaling receptors by agents like IL-6. However, SHP-2 and suppressor of cytokine signaling 3 (SOCS-3) are negative regulators of gp130 and inhibit STAT3 activation. The study by Han et al demonstrated that GH administration is associated with weight gain and improvement in colon histology in IL-10 null mice with colitis (Figure 5). GH also inhibited apoptosis and increased proliferation of crypt epithelial cells, while increasing apoptosis of lamina propria mononuclear cells – effects that were associated with SHP2:gp130 association and reduced colonic STAT3 activation. Similar findings were noted in colonic specimens from patients with Crohn’s disease. In the study by Theiss et al, the effects of GH treatment on mucosal inflammation and fibrosis were studied in an animal model of chronic, experimental granulomatous enterocolitis. One of the potential complications of GH treatment is exacerbation of intestinal fibrosis, which is a frequent development in patients with Crohn’s disease leading to stricture and fistula formation. Peptidoglycan-polysaccharide (PG-APS) or control human serum albumin (HSA) was injected into the cecum and ileum of rats to induce chronic enterocolitis. At the onset of reactivation of chronic inflammation in PG-APS groups, recombinant human GH or vehicle were administered for 14 days. In PG-APS-injected rats, GH improved a number of inflammatory complications, including reduced joint diameter, grossly detected adhesions, and mesenteric contractions, cecal fibrosis score, and collagen expression (Figure 6). This was associated with increased SOCS-3 mRNA and protein abundance in areas of increased collagen deposition. However, no effects on intestinal inflammation were observed. Both studies provide important insights into the mechanisms of GH action in mitigating the effects of intestinal inflammation. Moreover, GH does not appear to exacerbate fibrosis, but rather has anti-fibrogenic actions mediated by the induction of SOCS-3 expression. Collectively, these data provide promise and rational for GH as a novel mechanism of treating patients with IBD. Discovery and Identification of α-Defensins as Low Abundant, Tumor-Derived Serum Markers in Colorectal CancerGastroenterologyVol. 129Issue 1PreviewBackground & Aims: Although colorectal cancer is one of the best characterized tumors with regard to the multistep genetic progression, it remains one of the most frequent and deadly neoplasms in Western countries. This is mainly due to the fact that, up to now, no clinically relevant serum markers could be established in an early routine diagnostic procedure. Methods: We comparatively analyzed microdissected normal and tumorous colonic epithelium by ProteinChip technology to detect proteins specific for the tumor directly in the tissue. Full-Text PDF The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort StudyGastroenterologyVol. 129Issue 1PreviewBackground & Aims: The natural history of nonalcoholic fatty liver disease (NAFLD) in the community remains unknown. We sought to determine survival and liver-related morbidity among community-based NAFLD patients. Methods: Four hundred twenty patients diagnosed with NAFLD in Olmsted County, Minnesota, between 1980 and 2000 were identified using the resources of the Rochester Epidemiology Project. Medical records were reviewed to confirm diagnosis and determine outcomes up to 2003. Overall survival was compared with the general Minnesota population of the same age and sex. Full-Text PDF Anti-apoptotic Effects of L-Glutamine—Mediated Transcriptional Modulation of the Heat Shock Protein 72 During Heat ShockGastroenterologyVol. 129Issue 1PreviewBackground & Aims: During physiologic stress, L-glutamine becomes conditionally essential. Its deficiency results in altered epithelial barrier competence, bacterial translocation, and decreased survival. L-glutamine may attenuate these effects by modulating heat shock protein expression, a well-described effect in vitro. We sought to characterize L-glutamine-dependent transcriptional regulation in heat-shocked intestinal cells and to determine its physiologic relevance. Methods: IEC-18 and H4 intestinal cells were used. Full-Text PDF Growth Hormone Inhibits Signal Transducer and Activator of Transcription 3 Activation and Reduces Disease Activity in Murine ColitisGastroenterologyVol. 129Issue 1PreviewBackground & Aims: Constitutive signal transducer and activator of transcription (STAT) 3 activation promotes chronic inflammation and epithelial proliferation in murine colitis and human inflammatory bowel disease. SHP-2, through binding to the glycoprotein 130 signaling receptor, negatively regulates STAT3 activation. Growth hormone reduces disease activity and promotes mucosal healing in colitis and can activate SHP-2. Methods: We hypothesized that growth hormone administration would reduce disease activity in experimental colitis and that this would involve modulation of SHP-2/glycoprotein 130 association and STAT3 activation. Full-Text PDF Growth Hormone Reduces the Severity of Fibrosis Associated With Chronic Intestinal InflammationGastroenterologyVol. 129Issue 1PreviewBackground & Aims: Growth hormone (GH) is used to treat growth delay in children with Crohn’s disease and in patients with short-bowel syndrome. GH can increase collagen accumulation in intestinal mesenchymal cells, raising concern that GH therapy could exacerbate fibrosis in patients with Crohn’s disease. We tested if GH treatment altered inflammation or fibrosis during chronic, experimental granulomatous enterocolitis. Methods: Ileum and cecum of Lewis rats were subserosally injected with peptidoglycan-polysaccharide (PG-APS) or control human serum albumin. Full-Text PDF