Corneal Graft Rejection: Is it Reflected in Peripheral Immune Cells? Results of a Prospective Multicenter Study (VISICORT).

Background: Allogeneic graft rejection is the leading cause of graft failure in corneal transplantation (CT) despite the immune privilege of the anterior chamber and corneal bed. The ability to identify patients at higher risk of acute rejection before or after CT could have a major impact on the clinical management of these patients.

Methods: To address this important issue, a multicenter European cohort of low-risk (n = 142) and high-risk (n = 102) CT recipients was established, and the immune system was evaluated in detail in peripheral blood mononuclear cells and plasma before and 6 and 12 mo posttransplantation.

Sickle Cell Retinopathy Lost to Follow-up Study.

Purpose: To determine the outcomes of sickle cell retinopathy (SCR) patients who experienced at least one episode of being lost to follow-up (LTFU) compared to those who attended all appointments.

Methods: Adult SCR patients who visited Wills Eye Hospital Retina service (January 2012-December 2021) with >2 visits were reviewed for LTFU events, defined as failure to return for a follow-up appointment within 6 months of the scheduled date.

Results: One hundred and eighty-one eyes of 94 patients were included.

PROTECTION OF MICE AGAINST CECAL LIGATION AND PUNCTURE-INDUCED POLYMICROBIAL SEPSIS BY A FASCIOLA HEPATICA HELMINTH DEFENSE MOLECULE.

Sepsis results from a dysregulated host immune response to infection and is responsible for ~11 million deaths each year. In the laboratory, many aspects of sepsis can be replicated using a cecal ligation and puncture model, which is considered the most clinically relevant rodent model of sepsis. In the present study, histological and biomarker multiplex analyses revealed that the cecal ligation and puncture model initiated a large-scale inflammatory response in mice by 24 h, with evidence of acute organ damage by 48-72 h.

The impact of social deprivation on development and progression of diabetic kidney disease.

Introduction: Diabetes is one of the leading causes of chronic kidney disease. Social deprivation is recognised as a risk factor for complications of diabetes, including diabetic kidney disease. The effect of deprivation on rate of decline in renal function has not been explored in the Irish Health System to date.

Outcomes after reversed corneal graft rejection: a report from the European VISICORT project.

Objective: This study aims to describe the outcome of corneal grafts, both low risk and high risk, after successfully reversed immunological rejection.

Methods: Datasets on reversed rejection episodes in penetrating and endothelial keratoplasties between 2014 and 2019 (n=876) were extracted from the Adverse Immune Signatures and their Prevention in Corneal Transplantation database, which contains the prospectively and consecutively collected corneal transplants from five European centres. Stratified by the preoperatively determined risk status for immunological rejection, the outcome parameters analysed included visual acuity, intraocular pressure, endothelial cell density and central corneal thickness before and after reversed rejection episodes.

Human umbilical cord-derived mesenchymal stromal cells improve myocardial fibrosis and restore miRNA-133a expression in diabetic cardiomyopathy.

Background: Diabetic cardiomyopathy (DCM) is a serious health-threatening complication of diabetes mellitus characterized by myocardial fibrosis and abnormal cardiac function. Human umbilical cord mesenchymal stromal cells (hUC-MSCs) are a potential therapeutic tool for DCM and myocardial fibrosis via mechanisms such as the regulation of microRNA (miRNA) expression and inflammation. It remains unclear, however, whether hUC-MSC therapy has beneficial effects on cardiac function following different durations of diabetes and which mechanistic aspects of DCM are modulated by hUC-MSC administration at different stages of its development.

Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression.

Trastuzumab deruxtecan (T-DXd; DS-8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)-directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T-DXd was administered in tumor-bearing mice carrying NCI-N87, Capan-1, JIMT-1, and MDA-MB-468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T-DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response.

Amelioration of diabetic nephropathy in mice by a single intravenous injection of human mesenchymal stromal cells at early and later disease stages is associated with restoration of autophagy.

Background And Aims: Mesenchymal stromal cells (MSCs) a potentially effective disease-modulating therapy for diabetic nephropathy (DN) but their clinical translation has been hampered by incomplete understanding of the optimal timing of administration and in vivo mechanisms of action. This study aimed to elucidate the reno-protective potency and associated mechanisms of single intravenous injections of human umbilical cord-derived MSCs (hUC-MSCs) following shorter and longer durations of diabetes.

Methods: A streptozotocin (STZ)-induced model of diabetes and DN was established in C57BL/6 mice.

Social deprivation and diabetic kidney disease: A European view.

There is a large body of literature demonstrating a social gradient in health and increasing evidence of an association between social deprivation and diabetes complications. Diabetic kidney disease (DKD) increases mortality in people with diabetes. Socioeconomic deprivation is increasingly recognized as a modifier of risk factors for kidney disease but also an independent risk factor itself for kidney disease.

Intra-Aortic Balloon Pump Exacerbates Left Ventricular Outflow Tract Obstruction in a Patient With Takotsubo and Hypertrophic Cardiomyopathy.

• Obstructive HCM with superimposed takotsubo syndrome led to shock. • The use of an IABP worsened outflow obstruction. • Putting the IABP on standby improved outflow tract gradients dramatically.

Revisiting regulatory T cells as modulators of innate immune response and inflammatory diseases.

Regulatory T cells (Treg) are known to be critical for the maintenance of immune homeostasis by suppressing the activation of auto- or allo-reactive effector T cells through a diverse repertoire of molecular mechanisms. Accordingly, therapeutic strategies aimed at enhancing Treg numbers or potency in the setting of autoimmunity and allogeneic transplants have been energetically pursued and are beginning to yield some encouraging outcomes in early phase clinical trials. Less well recognized from a translational perspective, however, has been the mounting body of evidence that Treg directly modulate most aspects of innate immune response under a range of different acute and chronic disease conditions.

Physicochemical cues are not potent regulators of human dermal fibroblast trans-differentiation.

Due to their inherent plasticity, dermal fibroblasts hold great promise in regenerative medicine. Although biological signals have been well-established as potent regulators of dermal fibroblast function, it is still unclear whether physiochemical cues can induce dermal fibroblast trans-differentiation. Herein, we evaluated the combined effect of surface topography, substrate rigidity, collagen type I coating and macromolecular crowding in human dermal fibroblast cultures.

Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization.

Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota.

Functional glycoproteomics by integrated network assembly and partitioning.

The post-translational modification (PTM) of proteins by O-linked β--acetyl-D-glucosamine (O-GlcNAcylation) is widespread across the proteome during the lifespan of all multicellular organisms. However, nearly all functional studies have focused on individual protein modifications, overlooking the multitude of simultaneous O-GlcNAcylation events that work together to coordinate cellular activities. Here, we describe etworking of nteractors and ubstrats (NISE), a novel, systems-level approach to rapidly and comprehensively monitor O-GlcNAcylation across the proteome.

ANCA-associated vasculitis in Ireland: a multi-centre national cohort study.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease. There is a need for interoperable national registries to enable reporting of real-world long-term outcomes and their predictors in AAV. The Irish National Rare Kidney Disease (RKD) registry was founded in 2012.

Chemoproteomics reveals microbiota-derived aromatic monoamine agonists for GPRC5A.

The microbiota generates diverse metabolites to modulate host physiology and disease, but their protein targets and mechanisms of action have not been fully elucidated. To address this challenge, we explored microbiota-derived indole metabolites and developed photoaffinity chemical reporters for proteomic studies. We identified many potential indole metabolite-interacting proteins, including metabolic enzymes, transporters, immune sensors and G protein-coupled receptors.

-Arylpyrazole NOD2 Agonists Promote Immune Checkpoint Inhibitor Therapy.

The characterization of microbiota mechanisms in health and disease has reinvigorated pattern recognition receptors as prominent targets for immunotherapy. Notably, our recent studies on species revealed peptidoglycan remodeling and activation of NOD2 as key mechanisms for microbiota enhancement of immune checkpoint inhibitor therapy. Inspired by this work and other studies of NOD2 activation, we performed in silico ligand screening and developed -arylpyrazole dipeptides as novel NOD2 agonists.

Dietary counselling to reduce moderate sodium intake: effects on cardiovascular and renal biomarkers: primary findings of the COSIP and STICK phase II feasibility randomised controlled trials.

Background: While low sodium intake (<2.3 g/day) is recommended, there is uncertainty about long-term feasibility and effects on cardiorenal biomarkers in populations with moderate intake.

Methods: In two phase IIb, feasibility, randomised, parallel, open-label, controlled, single-centre trials, individuals aged >40 years with stable blood pressure (BP), without heart failure or postural hypotension were randomised to intensive dietary counselling (target sodium intake <2.