Specificities of human tap alleles for HLA—B27 binding peptides

Objective. Allelic TAP polymorphism has been linked to susceptibility to Reiter's syndrome and was suggested to influence disease phenotype in HLA-B27 positive patients with ankylosing spondylitis. In the present study, we examined whether the human TAP alleles functionally differ in their translocation specificity for HLA-B27-binding nonamers. Methods. TAP translocation of a panel of HLA-B27-binding peptides was measured with a labeled reporter peptide containing an N-linked glycosylation acceptor site in streptolysin O-permeabilized cells with different TAP alleles. Results. The different human TAP alleles tested did not measurably differ in their peptide specificity. Conclusion. The polymorphism of human TAP does not affect the translocated repertoire of HLA-B27 ligands and is therefore unlikely to play a decisive role in the development of HLA-B27-associated disease.     

Intranasal Delivery of a Methyllanthionine-Stabilized Galanin Receptor-2-Selective Agonist Reduces Acute Food Intake

The regulatory (neuro)peptide galanin is widely distributed in the central and peripheral nervous systems, where it mediates its effects via three G protein-coupled receptors (GAL_1-3R). Galanin has a vast diversity of biological functions, including modulation of feeding behavior. However, the clinical application of natural galanin is not practicable due to its rapid in vivo breakdown by peptidases and lack of receptor subtype specificity. Much effort has been put into the development of receptor-selective agonists and antagonists, and while receptor selectivity has been attained to some degree, most ligands show overlapping affinity. Therefore, we aimed to develop a novel ligand with specificity to a single galanin receptor subtype and increased stability. To achieve this, a lanthionine amino acid was enzymatically introduced into a galanin-related peptide. The residue’s subsequent cyclization created a conformational constraint which increased the peptide’s receptor specificity and proteolytic resistance. Further exchange of certain other amino acids resulted in a novel methyllanthionine-stabilized galanin receptor agonist, a G1pE-T3N-S6A-G12A-methyllanthionine[13–16]-galanin-(1–17) variant, termed M89b. M89b has exclusive specificity for GAL₂R and a prolonged half-life in serum. Intranasal application of M89b to unfasted rats significantly reduced acute 24 h food intake inducing a drop in body weight. Combined administration of M89b and M871, a selective GAL₂R antagonist, abolished the anorexigenic effect of M89b, indicating that the effect of M89b on food intake is indeed mediated by GAL₂R. This is the first demonstration of in vivo activity of an intranasally administered lanthipeptide. Consequently, M89b is a promising candidate for clinical application as a galanin-related peptide-based therapeutic.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01155-x.     

The second round of the Dutch colorectal cancer screening program: Impact of an increased fecal immunochemical test cut-off level on yield of screening

The Dutch colorectal cancer (CRC) screening program started in 2014, inviting the target population biennially to perform a fecal immunochemical test (FIT). We obtained prospectively collected data from the national screening information-system to present the results of the second round (2016) and evaluate the impact of increasing the FIT cut-off halfway through the first round from 15 to 47 μg Hb/g feces on outcomes in the second round. Second round screening was done with a 47 μg Hb/g feces FIT cut-off. Participants were classified based on first round participation status as either FIT (15,47) or FIT (47,47) participants, and previous nonparticipants. In total, 348,891 (75.9%) out of 459,740 invitees participated in the second round. Participation rates were 93.4% among previous participants and 21.0% among previous non-participants. FIT(47,47) participants had a significantly higher detection rate of AN (15.3 vs. 10.4 per 1,000 participants) compared to FIT(15,47) participants in the second round, while their cumulative detection rate of AN over two rounds was significantly lower (45.6 vs. 52.6 per 1,000 participants). Our results showed that participation in the Dutch CRC screening program was consistently high and that second round detection rates depended on the first round FIT cut-off. The cumulative detection over two rounds was higher among FIT(15,47) participants. These findings suggest that a substantial part of, but not all the missed findings in the first round due to the increased FIT cut-off were detected in the subsequent round.     

A short course of corticosteroids prior to surveillance colonoscopy to decrease mucosal inflammation in inflammatory bowel disease patients: Results from a randomized controlled trial

BackgroundInflammation is a known pitfall of surveillance colonoscopy for inflammatory bowel disease (IBD) as it is difficult to differentiate between inflammation and true dysplasia. This randomized controlled trial assessed the effectiveness of a low dose of corticosteroids prior to surveillance colonoscopy to decrease mucosal inflammation.MethodsIBD-patients scheduled for surveillance colonoscopy between July 2008–January 2010 were eligible to participate. Patients were randomized to either two weeks daily 20 mg prednisone and calcium plus vitamin D prior to surveillance colonoscopy or no treatment. All biopsies were reviewed by an expert gastrointestinal pathologist who was blinded for medication-use. Statistics were performed using chi-square tests, non-parametric tests and binary logistic regression.ResultsSixty patients (M/F 30/30, UC/CD 31/29) participated: 31 (52%) in the treatment arm and 29 (48%) in the control group. In the treatment arm, 247 biopsies were scored against 262 in the control group. In the treatment arm 27 out of 247 biopsies (10.9%) had a score > 1 on the Geboes scale, against 50 out of 262 biopsies (19.1%) in the control group, p = 0.013. In total, 58% of the treatment arm against 66% of the control group had endoscopic or histological mucosal inflammation (p = 0.6). There was a trend for patients in the treatment arm to have less severe inflammation compared with the control group, however this was not significant (p = 0.12).ConclusionsIn our cohort, a short course of corticosteroids decreases the overall histological disease activity in individual biopsies without major side-effects. Moreover, there is a trend for corticosteroids to decrease the maximum severity of both endoscopic and histological disease activity per patient.