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ZED1227 is a small molecule tissue transglutaminase (TG2) inhibitor. The compound selectively binds to the active state of TG2, forming a stable covalent bond with the cysteine in its catalytic center. The molecule was designed for the treatment of celiac disease. Celiac disease is an autoimmune-mediated chronic inflammatory condition of the small intestine affecting about 1–2% of people in Caucasian populations. The autoimmune disease is triggered by dietary gluten. Consumption of staple foods containing wheat, barley, or rye leads to destruction of the small intestinal mucosa in genetically susceptible individuals, and this is accompanied by the generation of characteristic TG2 autoantibodies. TG2 plays a causative role in the pathogenesis of celiac disease. Upon activation by Ca2+, it catalyzes the deamidation of gliadin peptides as well as the crosslinking of gliadin peptides to TG2 itself. These modified biological structures trigger breaking of oral tolerance to gluten, self-tolerance to TG2, and the activation of cytotoxic immune cells in the gut mucosa. Recently, in an exploratory proof-of-concept study, ZED1227 administration clinically validated TG2 as a “druggable” target in celiac disease. Here, we describe the specific features and profiling data of the drug candidate ZED1227. Further, we give an outlook on TG2 inhibition as a therapeutic approach in indications beyond celiac disease.

PurposeRepeated gadolinium-based contrast agent (GBCA)-enhanced MRIs are crucial in the diagnosis and follow-up of oncologic and chronic disorders in pediatric patients. The aim of the study was to evaluate the frequency and severity of adverse reactions to GBCAs in children after a single vs. multiple GBCA-enhanced abdomen MRIs.Material and methodsAll pediatric patients with at least one GBCA-enhanced abdominal MRI between 2009 and 2020 were retrospectively evaluated based on adverse reactions reports, according to the classification system of the American College of Radiology and guidelines on contrast agents of the European Society of Urogenital Radiology. A Student´s t-test analysis, a spearman ρ-correlation and a Chi-square test between the reported adverse reactions and the total number of GBCA applications, and the number of each applied GBCA was calculated. A p-value ResultsOf 623 patients with 964 GBCA-enhanced abdomen MRIs, there were 464 patients with only one and 159 patients with multiple GBCA administrations. Of 964 GBCA doses administrated, two cases with urticaria (mild allergy-like adverse reaction) and one case with vomiting (mild chemotoxic adverse reaction) were recorded (3/964 = 0.31%), but all the reports were in patients with multiple GBCA administration (3/159 = 1.89%). No adverse reactions in patients with a single GBCA administration were observed. The reported adverse reactions correlated significantly with the total number of GBCAs (pConclusionGBCA-associated adverse reactions are rare and mostly mild, but initially well-tolerated GBCA could cause adverse reactions due to the increase likelihood of drug hypersensitivity upon repeated GBCA exposure.

Organic molecules that can access various redox states have potential applications in electronics, batteries, catalysis, among others. Here the authors report the preparation of an unsymmetrical organoboron analogue of Thiele’s hydrocarbon and study its one- and two-electron oxidation reactions; remarkably, the radical cation is stable over a redox range of > 1 V and can also be isolated.

(1) Background: Progressive familial intrahepatic cholestasis (PFIC) is a rare cause of liver failure. Surgical biliary diversion (SBD) and ileal bile salt inhibitors (IBAT) can delay or prevent liver transplantation (LTX). A comparison of the two methodologies in the literature is lacking. The combination has not been investigated. (2) Methods: We performed a literature survey on medical and surgical treatments for PFIC and reviewed the charts of our patients with PFIC of a tertiary hospital. The end points of our analysis were a decrease in serum bile acid (sBA) levels, reduction of pruritus and delay or avoidance of (LTX). (3) Results: We included 17 case series on SBD with more than 5 patients and a total of 536 patients. External or internal SBD, either conventional or minimally invasive, can reduce pruritus and sBA, but not all PFIC types are suitable for SBD. Six publications described the use of two types of IBAT in PFIC with a total of 118 patients. Treatment response was dependent on genetic type and subtype. Patients with PFIC 2 (nt-BSEP) showed the best response to treatment. Four out of eleven PFIC patients underwent SBD at our centre, with two currently receiving IBAT. (4) Conclusions: Limited data on IBAT in selected patients with PFIC show safety and effectiveness, although surgical methods should still be considered as a successful bridging procedure. Further studies to evaluate a possible combination of IBAT and SBD in PFIC are warranted and treatment decision should be discussed in an interdisciplinary board.

BackgroundFactor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data.MethodsA total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR).ResultsEight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters.ConclusionsOur observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

Abstract Background Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. Results One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. Conclusions In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10–15% of IC-MPGN/C3G patients.

Der Beitrag fragt auf der Basis einer empirischen Fallstudie in der Landesbank Berlin nach Ansatzpunkten und Barrieren für die Durchsetzung von mehr Geschlechtergerechtigkeit im Bankensektor. In einer integralen Perspektive auf Erwerbsarbeit und Leben werden sowohl strukturelle Bedingungen betrieblicher Gleichstellungspolitik und Organisationsentwicklung als auch Geschlechterarrangements und subjektive Handlungsorientierungen der von uns befragten Führungskräfte rekonstruiert. Unsere These lautet, dass insbesondere weibliche, zunehmend aber auch jüngere männliche Führungskräfte eine „reflexive Karriereorientierung“ ausbilden, innerhalb derer ein stärker egalitäres Geschlechterverhältnis sowie persönliche Gestaltungsspielräume in- und außerhalb der Erwerbsarbeit eingefordert werden. Daraus könnten neue Interessenkoalitionen für eine bessere betriebliche Anerkennung von Reproduktionsbedürfnissen erwachsen. Allerdings bleiben diese geschlechterpolitischen Potenziale angesichts des hohen Rendite- und Kostendrucks im chronisch krisenhaften Finanzmarktkapitalismus bisher blockiert.

BACKGROUND: The angiotensin II receptor subtype 2 (AT2 receptor) is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear. METHODOLOGY/PRINCIPAL FINDINGS: Hearts from 1, 7, 14 and 56 days old wild-type (WT) and AT2 receptor-deficient (KO) mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of α-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca(2+) transient in response to isoprenaline when stimulated concomitantly with angiotensin II. CONCLUSION: The AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart.