In a clinical trial, the combination of ombitasvir, paritaprevir, and ritonavir, administered with dasabuvir, led to an SVR12 in 90% of patients with HCV genotype 1 infection and stage 4 or 5 CKD. The regimen is well tolerated, though RBV use may require a reduction or interruption to manage anemia. ClinicalTrials.gov ID NCT02207088.
SUMMARY
Glucagon-like peptide-1 (GLP-1), an insulinotropic peptide released from the intestine after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β-cells, we developed mice with β-cell specific knockdown of Glp1r. β-cell Glp1r knockdown mice had impaired GT after intraperitoneal (IP) glucose, and did not secrete insulin in response to IP or intravenous GLP-1. However, they had normal GT after oral glucose, a response that was impaired by a GLP1R antagonist. β-cell Glp1r knockdown mice had blunted responses to a GLP1R agonist, but intact glucose lowering with a DPP-4 inhibitor. Thus, in mice, β-cell Glp1r are required to respond to hyperglycemia and exogenous GLP-1, but other factors compensate for reduced GLP-1 action on the β-cell during meal ingestion. These results support a role for extra-islet GLP1R in oral glucose tolerance and paracrine regulation of β-cells by islet GLP-1.
Background & Aims
Hepatic elastography (HE) is a non-invasive technique that measures liver stiffness and is used to diagnose hepatic fibrosis. It can help patients thought to have early-stage disease avoid a staging liver biopsy, but only when confounding variables that increase liver stiffness are excluded. Chronic inflammation from hepatitis C virus (HCV) infection is not considered to be one of these variables.
Methods
We identified 684 patients with HCV and METAVIR fibrosis scores of 0–2 from a prospective, multi-institutional study of liver stiffness in 2880 patients with chronic liver disease.
Patients were 49.6±9.0 years old, 64.3% male, and had an average body mass index of 26.7±4.1.
Results
In a multivariate analysis, inflammation (based on histologic analysis) and level of alanine aminotransferase (ALT) were associated with liver stiffness. The chances of a patient having a level of stiffness that indicates cirrhosis increased with grade of inflammation and level of ALT. Using a conservative, 14.5 kPa cutoff for the diagnosis of cirrhosis, grade 3 inflammation had an odds ratio (OR) of 9.10 (95% confidence interval [CI], 2.49–33.4). Likewise, levels of ALT greater than 80 IU/L and 120 IU/L had ORs of 3.84 (95% CI, 2.10–7.00) and 4.10% (95% CI, 2.18– 7.69), respectively. The effect of the level of ALT persisted when analysis was restricted to patients with fibrosis scores of F0 to F1.
Conclusion
In patients with HCV infection and early-stage fibrosis, increased levels of ALT correlate with liver stiffness among patients in the lowest strata of fibrosis (METAVIR scores 0–2). Patients without fibrosis but high levels of ALT could have liver stiffness within the range for cirrhosis. Inflammation should be considered a confounding variable in analysis of liver stiffness.
One of the most serious complications faced by inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small non-protein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC, from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were up-regulated from non-neoplastic tissue to dysplasia, but down-regulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (p<0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (p<0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was down-regulated in both cell lines transfected with let-7e (p<0.05) as well as in HCT-116 cells transfected with miR-17 (p<0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was down-regulated in both cell lines (p<0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines.
One of the most serious complications faced by inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small non-protein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC, from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were up-regulated from non-neoplastic tissue to dysplasia, but down-regulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (p<0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (p<0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was down-regulated in both cell lines transfected with let-7e (p<0.05) as well as in HCT-116 cells transfected with miR-17 (p<0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was down-*
Transplantation is the treatment of choice for hepatocellular carcinoma (HCC) meeting the Milan criteria. HCC and chronic liver diseases have distinct natural histories for which an equitable transplant policy must account. We enrolled and prospectively followed at a single center 206 consecutive HCC patients that presented within the Milan criteria. Patients were treated per the Barcelona Clinic Liver Cancer (BCLC) algorithm; 95% received resection, ablation, or transarterial chemoembolization. The median follow-up was 16 months. Progression occurred in 84 patients, and 8 patients died. Risk factors for the time to disease progression (death or progression beyond T2) were analyzed in 170 patients with a complete data set. Risk factors with the strongest relationship to progression included tumor diameter and tumor persistence/recurrence after local therapy (hazard ratios of 1.51 and 2.75, respectively, when transplanted patients were censored at the time of transplantation and hazard ratios of 1.53 and 3.66, respectively, when transplantation was counted as an event; P 0.0001). To evaluate the current Model for End-Stage Liver Disease (MELD) exception, we compared the expected progression rate (PR) with our observed PR in 133 stage T2 patients. The current policy resulted in a large overestimation of the PR for T2 HCC and an unsatisfactory performance [Harrell's concordance index (C index) ¼ 0.60, transplant censored; C index ¼ 0.55, transplant as progression]. Risk factors for progression that were identified by univariate analysis were considered for multivariate analysis. With these risk factors and the patients' natural MELD scores, an adjusted model applicable to organ allocation was generated, and this decreased the discrepancy between the expected and observed PRs (C index ¼ 0.66, transplant censored; C index ¼ 0.69, transplant as progression). In conclusion, the current MELD exception largely overestimates progression in T2 patients treated according to the BCLC guidelines. The tumor response to resective or ablative treatment can predict tumor progression beyond the Milan criteria, and it should be taken into account in models designed to prioritize organ allocation. Liver Transpl 16:503-512,
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