Increased hepatic Akt phosphorylation alleviated glucose intolerance and improved liver function in leptin-deficient mice.

Aim of the study: Akt is involved in upregulating the insulin-signaling pathways essential for maintaining glucose metabolism. Glycosphingolipids are involved in the pathogenesis of glucose intolerance and associated target organ injury. On the other hand, oral administration of b-glucosylceramide (GC) has been shown to alleviate insulin resistance. The present study aimed to determine the effects of oral administration of insulin and GC, separately and in combination, on Akt expression and the subsequent effect on metabolic syndrome characteristics in leptin-deficient mice. Material and methods: Four groups of leptin-deficient ob/ob mice were orally administered for four weeks: vehicle, GC, short-acting insulin, and GC combined with insulin. Mice were followed for hepatic Akt expression and changes in tumor necrosis factor a (TNF-a) level, hyperlipidemia, and liver damage. Results: In mice that received insulin or GC, particularly those that received both, the liver phosphorylation of Akt was significantly increased compared to those that received only vehicle. Serum TNF-a levels decreased in insulin-treated mice. These effects were associated with alleviating glucose intolerance and hyperlipidemia, as manifested by a significant glucose tolerance test improvement and reductions in serum triglyceride and cholesterol levels. Significant liver damage alleviation was noted by liver enzyme reductions in all treated groups, along with liver steatosis in the insulin-treated mice. Conclusions: These data established the potential use of oral insulin administration with glycosphingolipids to alleviate glucose intolerance and associated liver damage and hyperlipidemia via increased Akt expression in the liver. The data support targeting Akt as a potent therapeutic target for metabolic syndrome.

Steroid-mediated liver steatosis is CD1d-dependent, while steroid-induced liver necrosis, inflammation, and metabolic changes are CD1d-independent.

INTRODUCTION: Glucocorticoids contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Natural killer T cells play a role in the pathogenesis of NAFLD and response to steroids. The present study aimed to determine the role of CD1d in steroid-mediated metabolic derangement and the steroid-protective effect of glycosphingolipids. METHODS: Ten groups of mice were studied. Steroids were orally administered to C57BL/6 mice to assess the therapeutic effect of ß-glucosylceramide (GC) on the development of steroid-mediated liver damage and metabolic derangements. The role of CD1d in the pathogenesis of steroid-induced liver damage and in mediating the hepatoprotective effect of GC was studied in CD1d-/- mice. RESULTS: A model of oral administration of steroids was established, resulting in insulin resistance, hyperinsulinemia, hypertriglyceridemia, liver steatosis, and hepatocellular injury. Steroid administration to CD1d-/- mice was associated with hyperglycemia and hypertriglyceridemia. However, CD1d-/- mice did not manifest marked steroid-induced steatosis. GC treatment alleviated steroid-associated metabolic derangements and liver injury independent of CD1d expression. CONCLUSION: A steroid-mediated model of NAFLD and metabolic derangements was established in which steroid-mediated steatosis was CD1d-dependent while steroid-induced liver necrosis, inflammation, and metabolic changes were CD1d-independent, which may support a dichotomy between steatosis and steatohepatitis in NAFLD.

Corrigendum to: Assessment of Benefit of Advanced Inflammatory Bowel Disease Training: Challenges and Solutions.

[This corrects the article DOI: 10.1093/crocol/otaa019.].

Surveillance Endoscopy in the Management of Hereditary Diffuse Gastric Cancer Syndrome.

Hereditary diffuse gastric cancer (HDGC) syndrome results from a germline CDH1 mutation, and microscopic foci of signet-ring carcinoma cells (SRCC) are present in nearly all gastrectomy specimens.1 The lifetime risk of invasive gastric cancer (GC) has been thought to be 70%,2 but recent data have suggested a lower risk of 37%.3 Prophylactic total gastrectomy is considered the standard of care, but many patients choose surveillance endoscopy instead. We sought to define the outcomes in CDH1-positive individuals who pursued endoscopic surveillance.

The assembly of glycosphingolipid determines their immunomodulatory effect: A novel method for structure-based design of immunotherapy.

Structure-activity relationships provide insight into the binding interactions of beta-glycosphingolipids (GSLs) with both the TCR and the CD1d molecules, as well as the subsequent immunologic response of regulatory NKT cells. AIM: To determine the effects of synthetic GSL structures on their immune modulatory functions. METHODS: GSLs of various structures were tested in vitro and in an animal model of Concanavalin A (ConA) immune-mediated hepatitis. RESULTS: In vitro, using SV40 binding to live monkey CV1 cells, the l-threo stereoisomer of C8-ß-LacCer inhibits caveolar internalization, reducing viral binding to the cell surface. In vivo, in the ConA model, LR172, which has a saturated C8 chain, and LR178, which has a trans double bond at C-2 in the C8 chain, suppressed the immune-mediated liver inflammation and reduced IFNγ levels in a dose dependent manner. The beneficial effects of LR172 and of LR178 are associated with suppression of liver apoptosis, increased phosphorylated STAT3 expression in the liver, and an increase in the NKT liver/spleen ratio. SUMMARY: The assembly of GSLs determines their immunomodulatory effect and can serve as a method for structure-based design of immunotherapy.

Assessment of Benefit of Advanced Inflammatory Bowel Disease Training: Challenges and Solutions.

Background: Advanced inflammatory bowel disease (IBD) fellowships are available for gastroenterologists who wish to increase their expertise in complex IBD. However, little is known about the outcomes of such training. The aims of this study were to assess clinical and academic outcomes following advanced training in IBD. Methods: We surveyed gastroenterologists who completed advanced IBD fellowships and compared competency and outcomes to gastroenterologists focusing in IBD who completed gastroenterology training alone. Participants completed a survey via REDCap. Continuous variables were compared using the Wilcoxon rank-sum test. Categorical variables were compared using chi-square or Fisher's exact tests. Results: A total of 104 physicians participated in the study. IBD fellowships were completed by 31 physicians (30%), of whom 29 (94%) felt their training was excellent. Management of complicated IBD (84%), research mentoring (74%), and career mentoring (71%) were felt to contribute most highly to professional development. Compared to non-advanced trained physicians, advanced trained physicians expressed higher levels of comfort with management of IBD during pregnancy (P = 0.003), complicated IBD (P = 0.057), and peri-operative IBD (P = 0.057). No significant advantage was detected in academic productivity. Common barriers to participation in IBD fellowships included feeling it was unnecessary (45%) and desire to begin a faculty position (42%). Conclusions: This study suggests there may be clinical benefit to advanced IBD training. Importantly, this study identified that there are also unique challenges to the assessment of clinical competency in IBD training. Efforts by the IBD community to establish a registry of advanced trainees and improve competency assessments are needed.

Oral Administration of Hoodia parviflora Alleviates Insulin Resistance and Nonalcoholic Steatohepatitis.

Metabolic syndrome is recognized as a proinflammatory condition leading to hepatic steatosis and nonalcoholic steatohepatitis (NASH). We tested the effects of a succulent species Hoodia parviflora N.E. Br., of the genus Hoodia sweetex Dence, on animal models of NASH and insulin resistance (ob/ob mouse and the sand rat Psammomys obesus). IL6 secretion was evaluated by ELISA and hepatic signal transducer and activator of transcription 3 by Western blot. We followed liver enzymes, weight, glucose, hepatic histology, hepatic triglycerides (TGs), and total fat and serum insulin. Oral administration of extracts derived from H. parviflora alleviated the insulin resistance manifested by improved glucose tolerance tests. Treatment alleviated the liver injury noted by a decrease in liver enzyme levels, improved intrahepatic TG content, total hepatic fat, and improved hepatic histology. Similarly, treatment with H. parviflora reduced hepatic inflammation in mice with Concanavalin A-induced hepatitis. These effects were independent of food consumption and weight. H. parviflora was associated with alleviated insulin resistance, hepatic steatosis, and liver injury. The data support its use as a liver protector.

Publisher Correction: Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors.

Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered 'non-functional'1-3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and ß-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1- tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.

Comparative safety and effectiveness of tumor necrosis factor α antagonists and vedolizumab in elderly IBD patients: a multicentre study.

BACKGROUND: The older patient group with inflammatory bowel diseases (IBD) is particularly vulnerable to consequences of disease and therapy-related side effects but little is known about the best treatment options in this population. AIM: To compare safety and efficacy of tumor necrosis factor α antagonist (anti-TNF) or vedolizumab (VDZ) in patients with IBD >60 years of age. METHODS: This retrospective study included patients with Crohn's disease (CD) or ulcerative colitis (UC) initiating anti-TNF or VDZ therapy ≥60 years of age at three study sites. We examined occurrence of infection or malignancy within 1 year after therapy as our primary outcome. Our efficacy outcomes included clinical remission at 3, 6 and 12 months. Multivariable logistic regression models adjusting for relevant confounders estimated odds ratios (OR) and 95% confidence intervals. RESULTS: The study included 131 anti-TNF and 103 VDZ initiated patients (age range 60-88 years). Approximately half had CD. At 1 year, there were no significant differences in safety profile between the two therapeutic classes. Infections were observed in 20% of anti-TNF-treated and 17% of VDZ-treated patients (P = 0.54). Pneumonia was the most common infection in both groups. While more anti-TNF-treated CD patients were in remission at 3 months compared to VDZ (OR 2.82, 95% CI 1.18-6.76), this difference was not maintained at 6 and 12 months suggesting similar efficacy of both classes. CONCLUSIONS: Both anti-TNF and VDZ therapy were similarly effective and safe in elderly IBD patients.

Sleep Disturbances Can Be Prospectively Observed in Patients with an Inactive Inflammatory Bowel Disease.

BACKGROUND: Poor sleep quality is associated with adverse health consequences. Sleep disturbances can impact the immune function and inflammatory processes. Little is known about sleep disturbances in patients with inflammatory bowel disease (IBD), while not in flare, i.e., inactive. AIMS: To prospectively explore the sleep quality of patients with an inactive IBD. METHODS: This pilot study included 36 consecutive patients with IBD and 27 healthy volunteers. All IBD patients had an inactive disease. Participants underwent an overnight ambulatory polysomnography. Data on disease duration, medications, complications, and treatment were collected from the medical records. RESULTS: The mean age of the IBD and the control groups was 39 ± 15 and 34.6 ± 9.6 years. A significantly less rapid eye movement (REM) sleep was noted in the IBD group vs. control (23.7 vs. 27.8%, p = 0.047); light sleep percentage and REM latency were also longer in the IBD group. Moreover, oxygen desaturation below 90% was more common in the IBD group. All other sleep parameters including respiratory disturbance index, apnea-hypopnea index, number of wakes, sleep latency, and snoring strength were similar in both groups. CONCLUSIONS: Inactive IBD is associated with sleep disturbances. A larger prospective study should be conducted to confirm these findings.

Glycosphingolipids Prevent APAP and HMG-CoA Reductase Inhibitors-mediated Liver Damage: A Novel Method for "Safer Drug" Formulation that Prevents Drug-induced Liver Injury.

Background and Aims: Acetaminophen (APAP) and HMG-CoA reductase inhibitors are common causes of drug-induced liver injury (DILI). This study aimed to determine the ability to reduce APAP- and statins-mediated liver injury by using formulations that combine glycosphingolipids and vitamin E. Methods: Mice were injected with APAP or with statins and treated before and after with ß-glucosylceramide (GC), with or without vitamin E. Mice were followed for changes in liver enzymes, liver histology, hepatic expression of JNK, STAT3 and caspase 3, as well as intrahepatic natural killer T cells (NKT) and the serum cytokine levels by flow cytometry. Results: Administration of GC before or after APAP alleviated the liver damage, as noted by a reduction of the liver enzymes, improvement in the liver histology and decreased hepatic caspase 3 expression. Beneficial effect was associated with a reduction of the intrahepatic NKT, JNK expression in the liver, and increased glutathione in the liver, and decreased TNF-α serum levels. Synergistic effect of co-administration of GC with vitamin E was observed. Similar protective effect of GC on statin-mediated liver damage was documented by a reduction in liver enzymes and improved liver histology, which was mediated by reduction of NKT, increased STAT3 expression in the liver, and reduced the TGF-ß and IL17 levels. Conclusions: ß-glycosphingolipids exert a hepatoprotective effect on APAP- and statins-mediated liver damage. Vitamin E exerted a synergistic effect to that of GC. The generation of "safer drug" formulations, which include an active molecule combined with a hepatoprotective adjuvant, may provide an answer to the real unmet need of DILI.

Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Screening of all CRCs for LS is currently recommended, but screening of ECs is inconsistent. The objective of this study was to determine the added value of screening both CRC and EC tumors in the same population. METHODS: A prospective, immunohistochemistry (IHC)-based screening program for all patients with newly diagnosed CRCs and ECs was initiated in 2011 and 2013, respectively, at 2 centers (primary and tertiary). Genetic testing was recommended for those who had tumors with absent mutS homolog 2 (MSH2), MSH6, or postmeiotoic segregation increased 2 (PMS2) expression and for those who had tumors with absent mutL homolog 1 (MLH1) expression and no v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation or MLH1 promoter methylation. Amsterdam II criteria, revised Bethesda criteria, and scores from prediction models for gene mutations (the PREMM1,2,6 and PREMM5 prediction models) were ascertained in patients with LS. RESULTS: In total, 1290 patients with CRC and 484 with EC were screened for LS, and genetic testing was recommended for 137 patients (10.6%) and 32 patients (6.6%), respectively (P = .01). LS was identified in 16 patients (1.2%) with CRC and in 8 patients (1.7%) with EC. Among patients for whom genetic testing was recommended, the LS diagnosis rate was higher among those with EC (25.0% vs 11.7%, P = .052). The Amsterdam II criteria, revised Bethesda criteria, and both PREMM calculators would have missed 62.5%, 50.0%, and 12.5% of the identified patients with LS, respectively. CONCLUSIONS: Expanding a universal screening program for LS to include patients who had EC identified 50% more patients with LS, and many of these patients would have been missed by risk assessment tools (including PREMM5 ). Universal screening programs for LS should include both CRC and EC. Cancer 2018. © 2018 American Cancer Society.

Liver involvement in Gaucher disease - Review and clinical approach.

Gaucher disease (GD), one of the most prevalent lysosomal storage diseases, is associated with glucocerebroside accumulation in cells of the monocyte-macrophage system in various organs, including the liver. Evaluating and managing liver disease in patients with Gaucher disease may be challenging. While hepatic involvement is common in Gaucher disease, its severity, and clinical significance span a wide spectrum, ranging from sub-clinical involvement to liver cirrhosis with its associated complications including portal hypertension. Apart from liver involvement in Gaucher disease, patients with may also suffer from other comorbidities involving the liver. That Gaucher disease itself can mimic hepatic lesions, affect laboratory tests used to characterize liver disease, and may be associated with non-cirrhotic portal hypertension, complicates the diagnostic approach even more. Better understanding of liver involvement in Gaucher disease can spare patients unnecessary invasive testing, and assist physicians in decision making when evaluating patients with Gaucher disease suspected for significant liver disease. This review describes the various clinical manifestations, laboratory and imaging abnormalities that may be encountered when following patients with Gaucher disease for liver involvement. The mechanism for liver disease are discussed, as well as the possible hepato-protective effect of glucocerebroside, and the a diagnostic and treatment approaches.

Features of Patients With Hereditary Mixed Polyposis Syndrome Caused by Duplication of GREM1 and Implications for Screening and Surveillance.

Hereditary mixed polyposis syndrome is a rare colon cancer predisposition syndrome caused by a duplication of a noncoding sequence near the gremlin 1, DAN family BMP antagonist gene (GREM1) originally described in Ashkenazi Jews. Few families with GREM1 duplications have been described, so there are many questions about detection and management. We report 4 extended families with the duplication near GREM1 previously found in Ashkenazi Jews; 3 families were identified at cancer genetic clinics in Israel and 1 family was identified in a cohort of patients with familial colorectal cancer. Their clinical features include extracolonic tumors, onset of polyps in adolescence, and rapid progression of some polyps to advanced adenomas. One family met diagnostic criteria for Lynch syndrome. Expansion of the hereditary mixed polyposis syndrome phenotype can inform surveillance strategies for carriers of GREM1 duplications.

A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome.

To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients ≥70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, P<0.01). However, a hybrid approach that reserves MLH1 methylation testing for BRAF wild-type cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs.

A prospective study of fecal calprotectin and lactoferrin as predictors of small bowel Crohn's disease in patients undergoing capsule endoscopy.

BACKGROUND: Capsule endoscopy (CE) is often used to investigate small bowel Crohn's disease (CD). AIM: The aim of this study is to prospectively assess the value of fecal calprotectin and lactoferrin to predict CE findings. PATIENTS AND METHODS: Sixty-eight consecutive patients that were referred for CE were included. Stool samples for calprotectin and lactoferrin and blood samples were collected for relevant parameters. Correlation between fecal markers and CE findings was assessed and receiver operating characteristic (ROC) curves were built to determine the predictive values of fecal markers for the diagnosis of CD. RESULTS: Fecal calprotectin data was available for all the patients and lactoferrin data for 38. CE findings compatible with CD were found in 23 (33%) patients and 45 (67%) were negative for CD. The average age of the CD group was 34 compared to 46 in the non-CD group (p = .048). Median calprotectin and lactoferrin in the CD group and in the control group were 169 mg/kg vs. 40 (p = .004) and 6.6 mg/kg vs. 1 (p = .051), respectively. The area under the ROC curve was 0.767 for calprotectin and 0.70 for lactoferrin. A fecal calprotectin concentration of 95 mg/kg and fecal lactoferrin of 1.05 mg/kg had a sensitivity, specificity, positive predictive value and negative predictive value of 77 and 73%, 60 and 65%, 50 and 50%, and 84 and 84% in predicting CE findings compatible with CD. CONCLUSIONS: Fecal markers are simple and noninvasive surrogates for predicting CE findings compatible with CD. Fecal markers can help determine which patients should be referred for CE. ClinicalTrials.gov Identifier: NCT01266629.