Joel Pekow

Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C‐related cirrhosis

Chronic hepatitis C can result in fatty changes in the liver. Previous studies have suggested that hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with hepatitis C virus (HCV) infection. The authors sought to determine whether hepatic steatosis is associated with hepatocellular carcinoma (HCC) in a cohort of patients with hepatitis C‐related cirrhosis.

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohns disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4(+)CD45RB(hi) T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.

MicroRNAs in Inflammatory Bowel Disease

&NA; MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene and protein expression. miRNAs are critical to a normal immune response and have altered expression in multiple immune‐mediated disorders. This emerging role of miRNAs in the pathogenesis of multiple disease states has led to investigations into miRNA expression profiles in inflammatory bowel disease (IBD). The discovery of miRNAs in IBD is likely to contribute to our understanding of IBD pathogenesis and lead to clinical advances in IBD. This review focuses on miRNA expression in inflammation, autoimmune disorders, and inflammation‐associated cancer, as well as their function in the biology and management of IBD. (Inflamm Bowel Dis 2011;)

miR‐143 and miR‐145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes

Background: miR‐143 and miR‐145 are believed to function as colon cancer tumor suppressors, as they inhibit colon cancer cell growth and are downregulated in sporadic colonic tumors. We speculated that miR‐143 and miR‐145 might also be downregulated and contribute to malignant transformation of colonic epithelium in longstanding ulcerative colitis (UC). Methods: Biopsies were obtained 20 cm proximal to the anus from individuals with quiescent UC and from normal controls. RNA and proteins were extracted and measured. miR‐143 and miR‐145 were quantified by real‐time polymerase chain reaction (PCR) and miR‐145 was also assessed by in situ hybridization. Putative targets of these miRNAs, K‐RAS, API5, MEK‐2 (miR‐143), and IRS‐1 (miR‐145) were determined by western blotting. To assess the effects of miR‐143 and miR‐145 on these predicted targets, HCT116 and HCA‐7 colorectal cancer cells were transfected with miR‐143 and miR‐145 and expression levels of these proteins were measured. Results: In UC, miR‐143 and miR‐145 were significantly downregulated 8.3‐fold (3.4–20.1) (P < 0.0001) and 4.3‐fold (2.3–7.8) (P < 0.0001), respectively, compared to normal colon. In contrast, IRS‐1, K‐RAS, API5, and MEK‐2 were upregulated in UC, consistent with their assignments as targets of these miRNAs. Furthermore, transfected miR‐143 and miR‐145 significantly downregulated these proteins in HCT116 or HCA‐7 cells. Conclusions: Compared to normal colonic mucosa, in chronic UC miR‐143 and miR‐145 were significantly downregulated and their predicted targets, IRS‐1, K‐RAS, API5, and MEK‐2 were upregulated. We postulate that loss of these tumor suppressor miRNAs predispose to chronic inflammation and neoplastic progression in IBD. (Inflamm Bowel Dis 2011;)

EGFR Signals Downregulate Tumor Suppressors miR-143 and miR-145 in Western Diet–Promoted Murine Colon Cancer: Role of G1 Regulators

Epidermal growth factor receptors (EGFR) contribute to colonic tumorigenesis in experimental models of colon cancer. We previously showed that EGFR was also required for colonic tumor promotion by Western diet. The goal of this study was to identify EGFR-regulated microRNAs that contribute to diet-promoted colonic tumorigenesis. Murine colonic tumors from Egfrwt and hypomorphic Egfrwa2 mice were screened using micro RNA (miRNA) arrays and miR-143 and miR-145 changes confirmed by Northern, real-time PCR, and in situ analysis. Rodent and human sporadic and ulcerative colitis (UC)-associated colon cancers were examined for miR-143 and miR-145. Effects of EGFR on miR-143 and miR-145 expression were assessed in murine and human colonic cells and their putative targets examined in vitro and in vivo. miR-143 and miR-145 were readily detected in normal colonocytes and comparable in Egfrwt and Egfrwa2 mice. These miRNAs were downregulated in azoxymethane and inflammation-associated colonic tumors from Egfrwt mice but upregulated in Egfrwa2 tumors. They were also reduced in human sporadic and UC colon cancers. EGFR signals suppressed miR-143 and miR-145 in human and murine colonic cells. Transfected miR-143 and miR-145 inhibited HCT116 cell growth in vitro and in vivo and downregulated G1 regulators, K-Ras, MYC, CCND2, cdk6, and E2F3, putative or established targets of these miRNAs. miRNA targets Ras and MYC were increased in colonic tumors from Egfrwt but not Egfrwa2 mice fed a Western diet. EGFR suppresses miR-143 and miR-145 in murine models of colon cancer. Furthermore, Western diet unmasks the tumor suppressor roles of these EGFR-regulated miRNAs. Mol Cancer Res; 9(7); 960–75. ©2011 AACR.

Outcome after surveillance of low‐grade and indefinite dysplasia in patients with ulcerative colitis

Background: The management of low‐grade (LGD) and indefinite dysplasia (IND) in patients with ulcerative colitis (UC) remains controversial, as outcomes after a diagnosis of LGD or IND in previous studies vary widely. Methods: All patients evaluated were from a single institution referral center who had a history of UC and a diagnosis of either LGD or IND between 1994 and 2008 as confirmed by 2 expert gastrointestinal (GI) pathologists. Data were collected by chart review of electronic and paper medical records. All patients who did not undergo a colectomy within 90 days of their dysplasia diagnosis were included in the final analysis. Hazard ratios for risk factors as well as incidence rates and Kaplan–Meier estimates were used to calculate the progression to high‐grade dysplasia (HGD) or colorectal cancer (CRC). Results: Thirty‐five patients were included in the analysis, of whom 2 patients with IND and 2 patients with LGD developed HGD or CRC over a mean duration of 49.8 months. In total, the incident rate for advanced neoplasia for all patients was 2.7 cases of HGD or CRC per 100 person‐years at risk. For flat and polypoid LGD the incident rate of advanced neoplasia was 4.3 and 1.5 cases per 100 person‐years at risk, respectively. Patients with primary sclerosing cholangitis (PSC) had an incident rate of 10.5 cases per 100 years of patient follow‐up. Conclusions: We report a low rate of progression to HGD or CRC in patients who underwent surveillance for LGD or IND; polypoid dysplasia showed less risk of progression than flat dysplasia. (Inflamm Bowel Dis 2010)

The emerging role of miRNAs in inflammatory bowel disease: a review

Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn’s disease, is believed to develop as a result of a deregulated inflammatory response to environmental factors in genetically susceptible individuals. Despite advances in understanding the genetic risks of IBD, associated single nucleotide polymorphisms have low penetrance, monozygotic twin studies suggest a low concordance rate, and increasing worldwide IBD incidence leave gaps in our understanding of IBD heritability and highlight the importance of environmental influences. Operating at the interface between environment and heritable molecular and cellular phenotypes, microRNAs (miRNAs) are a class of endogenous, small noncoding RNAs that regulate gene expression. Studies to date have identified unique miRNA expression profile signatures in IBD and preliminary functional analyses associate these deregulated miRNAs to canonical pathways associated with IBD pathogenesis. In this review, we summarize and discuss the miRNA expression signatures associated with IBD in tissue and peripheral blood, highlight miRNAs with potential future clinical applications as diagnostic and therapeutic targets, and provide an outlook on how to develop miRNA based therapies.

Chitinase 3-Like-1 Expression in Colonic Epithelial Cells as a Potentially Novel Marker for Colitis-Associated Neoplasia

Chitinase 3-like-1 (CHI3L1/YKL-40) is a protein secreted from restricted cell types including colonic epithelial cells (CECs) and macrophages. CHI3L1 is an inflammation-associated molecule, and its expression is enhanced in persons with colitis and colon cancer. The biological function of CHI3L1 on CECs is unclear. In this study, we investigated the role of CHI3L1 on CECs during the development of colitis-associated neoplasia. We analyzed colonic samples obtained from healthy persons and from persons with ulcerative colitis with or without premalignant or malignant changes. DNA microarray and RT-PCR analyses significantly increased CHI3L1 expression in non-dysplastic mucosa from patients with inflammatory bowel disease (IBD) who had dysplasia/adenocarcinoma compared with that in healthy persons and in patients with IBD who did not have dysplasia. As determined by IHC, CHI3L1 was expressed in specific cell types in the crypts of colonic biopsies obtained from patients with ulcerative colitis who have remote dysplasia. Purified CHI3L1 efficiently activated the NF-κB signaling pathway and enhanced the secretion of IL-8 and TNF-α in SW480 human colon cancer cells. In addition, colon cancer cell proliferation and migration were significantly promoted in response to CHI3L1 in these cells. In summary, CHI3L1 may contribute to the proliferation, migration, and neoplastic progression of CECs under inflammatory conditions and could be a useful biomarker for neoplastic changes in patients with IBD.

The features of mucosa-associated microbiota in primary sclerosing cholangitis

Little is known about the role of the microbiome in primary sclerosing cholangitis.

Rescue therapy with cyclosporine or infliximab is not associated with an increased risk for postoperative complications in patients hospitalized for severe steroid-refractory ulcerative colitis.

Background:Cyclosporine and infliximab (IFX) are effective medical therapies for inducing remission in patients with steroid-refractory ulcerative colitis (UC). Patients with acute severe disease who do not respond to these therapies require colectomy, however, the risk of postoperative complications in such patients is not known. Analyzing patients with acute severe UC, we compared the incidence of postoperative complications in patients who failed rescue therapy with cyclosporine or IFX with that in patients who received intravenous (IV) corticosteroids alone. Methods:We performed a retrospective cohort study of UC patients who underwent colectomy after inpatient treatment with cyclosporine plus IV corticosteroids (CsA+IVS), infliximab plus IV corticosteroids (IFX+IVS), or IV corticosteroids alone (IVS) at the University of Chicago Hospitals from October 1, 2006 to October 1, 2012. Primary endpoints were infectious, noninfectious, and total complications occurring within 30 days of colectomy. Results:Of 78 patients, 19 were treated with CsA+IVS, 24 with IFX+IVS, 4 with both CsA and IFX+IVS, and 31 with IVS alone. Patients treated with rescue therapy plus IVS had no difference in total postoperative complications compared with those receiving IVS alone (CsA+IVS: relative risk (RR) = 0.63, 95% confidence interval (CI), 0.33–1.23; IFX+IVS: RR = 0.65, 95% CI, 0.36–1.17). There remained no difference in postoperative complications between the rescue therapy and IVS alone groups when subcategorizing overall complications into infectious (CsA+IVS: RR = 0.54, 95% CI, 0.17–1.76; IFX+IVS: RR = 0.86, 95% CI, 0.36–2.09) and noninfectious (CsA+IVS: RR = 0.88, 95% CI, 0.43–1.80; IFX+IVS: RR = 0.40, 95% CI, 0.15–1.07) causes. Conclusions:Cyclosporine and IFX are not associated with an increased risk for postoperative complications in patients hospitalized for severe UC refractory to corticosteroids.