MINCLE and TLR9 agonists synergize to induce Th1/Th17 vaccine memory and mucosal recall in mice and non-human primates.

Development of new vaccines tailored for difficult-to-target diseases is hampered by a lack of diverse adjuvants for human use, and none of the currently available adjuvants induce Th17 cells. Here, we develop a liposomal adjuvant, CAF®10b, that incorporates Mincle and Toll-like receptor 9 agonists. In parallel mouse and non-human primate studies comparing to CAF® adjuvants already in clinical trials, we report species-specific effects of adjuvant composition on the quality and magnitude of the responses.

Dune Hares: Population Indices, Home Range Size, and Habitat Selection of the European Hare on a Danish Island.

Population indices, such as transect counts of animals, can provide important information concerning population changes over time. Moreover, data concerning the home range size and habitat selection of individuals can provide valuable insight into spatial requirements of animals and how they can adapt to variable environments. Here, we describe the population development of European hares () and investigated home range sizes and habitat selection of six radio-tagged individuals on the small (80 ha) Danish Wadden Sea island Langli.

Impact of Manufacturing Process and Compounding on Properties and Quality of Follow-On GLP-1 Polypeptide Drugs.

Purpose: The prevalence of follow-on and compounded products of glucagon-like peptide-1 analogs is increasing. We assessed glucagon-like peptide-1 analogs semaglutide and liraglutide for purity, potential immunogenicity, and expected stability, by comparing a representative selection of commercially available follow-on drug substances (DSs) and drug products (DPs) with their corresponding originators.

Methods: Tests included several chromatography methods coupled with ultraviolet and mass spectrometry detectors, inductively coupled plasma optical emission spectroscopy, inductively coupled plasma mass spectrometry, nuclear magnetic resonance, dissolution analyses, in silico peptide/major histocompatibility complex II-binding prediction, and fibrillation assays.

Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation.

Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and -challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease.

A novel approach to deep venous arterialization using WavelinQ EndoAVF technology.

Deep venous arterialization is increasingly being considered for the management of patients with "no option chronic limb threatening ischemia" (CLTI) who would otherwise require a major limb amputation. WavelinQ (Becton Dickinson) is a new technology increasing in popularity for its role in the formation of endovascular arteriovenous fistulas but might well have applications in other areas of vascular surgery. We present a novel approach to deep venous arterialization using WavelinQ arteriovenous fistula technology for a patient with nonreconstructable chronic limb threatening ischemia experiencing both rest pain and forefoot gangrene.

Repeated immunization with ATRA-containing liposomal adjuvant transdifferentiates Th17 cells to a Tr1-like phenotype.

In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis. Th17 cells can transdifferentiate into other T cell subsets in inflammatory conditions, however, there have been no attempts to target Th17 cell plasticity using vaccines. We investigated if autoantigen-specific Th17 cells could be specifically targeted using a therapeutic vaccine approach, where antigen was formulated in all-trans retinoic acid (ATRA)-containing liposomes, permitting co-delivery of antigen and ATRA to the same target cell.

Co-adjuvanting DDA/TDB liposomes with a TLR7 agonist allows for IgG2a/c class-switching in the absence of Th1 cells.

Class-switching to IgG2a/c in mice is a hallmark response to intracellular pathogens. T cells can promote class-switching and the predominant pathway for induction of IgG2a/c antibody responses has been suggested to be via stimulation from Th1 cells. We previously formulated CAF®01 (cationic liposomes containing dimethyldioctadecylammonium bromide (DDA) and Trehalose-6,6-dibehenate (TDB)) with the lipidated TLR7/8 agonist 3M-052 (DDA/TDB/3M-052), which promoted robust Th1 immunity in newborn mice.

Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice.

Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as immune-responsive gene 1 [IRG1]), are upregulated during atherogenesis in mice.

Altered expression of the L-arginine/nitric oxide pathway in ovarian cancer: metabolic biomarkers and biological implications.

Motivation: Ovarian cancer (OC) is a highly lethal gynecological malignancy. Extensive research has shown that OC cells undergo significant metabolic alterations during tumorigenesis. In this study, we aim to leverage these metabolic changes as potential biomarkers for assessing ovarian cancer.

Qualification of the differential leukocyte count and immunophenotyping in cryopreserved ex vivo whole blood assay.

We developed a flow cytometry-based assay, termed Differential Leukocyte Counting and Immunophenotyping in Cryopreserved Ex vivo whole blood (DLC-ICE), that allows quantification of absolute counts and frequencies of leukocyte subsets and measures expression of activation, phenotypic and functional markers. We evaluated the performance of the DLC-ICE assay by determining inter-operator variability for processing fresh whole blood (WB) from healthy donors collected at multiple clinical sites. In addition, we assessed inter-operator variability for staining of fixed cells and robustness across different anticoagulants.

A protective, single-visit TB vaccination regimen by co-administration of a subunit vaccine with BCG.

The only licensed tuberculosis (TB) vaccine, Bacillus Calmette Guerin (BCG), fails to reliably protect adolescents and adults from pulmonary TB, resulting in ~1.6 million deaths annually. Protein subunit vaccines have shown promise against TB in clinical studies.

Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy.

Background: Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs).

An arginase1- and PD-L1-derived peptide-based vaccine for myeloproliferative neoplasms: A first-in-man clinical trial.

Introduction: Arginase-1 (ARG1) and Programed death ligand-1 (PD-L1) play a vital role in immunosuppression in myeloproliferative neoplasms (MPNs) and directly inhibit T-cell activation and proliferation. We previously identified spontaneous T-cell responses towards PD-L1 and ARG1 derived peptide epitopes in patients with MPNs. In the present First-in-Man study we tested dual vaccinations of ARG1- derived and PD-L1-derived peptides, combined with Montanide ISA-51 as adjuvant, in patients with Janus Kinase 2 (JAK2) V617F-mutated MPN.

A novel adjuvant formulation induces robust Th1/Th17 memory and mucosal recall responses in Non-Human Primates.

After clean drinking water, vaccination is the most impactful global health intervention. However, development of new vaccines against difficult-to-target diseases is hampered by the lack of diverse adjuvants for human use. Of particular interest, none of the currently available adjuvants induce Th17 cells.

Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function.

Preservation quality of donor hearts is a key determinant of transplant success. Preservation duration beyond 4 hours is associated with primary graft dysfunction (PGD). Given transport time constraints, geographical limitations exist for donor-recipient matching, leading to donor heart underutilization.

Reduced vitamin D-induced cathelicidin production and killing of in macrophages from a patient with a non-functional vitamin D receptor: A case report.

Tuberculosis (TB) presents a serious health problem with approximately a quarter of the world's population infected with () in an asymptomatic latent state of which 5-10% develops active TB at some point in their lives. The antimicrobial protein cathelicidin has broad antimicrobial activity towards viruses and bacteria including . Vitamin D increases the expression of cathelicidin in many cell types including macrophages, and it has been suggested that the vitamin D-mediated antimicrobial activity against is dependent on the induction of cathelicidin.

Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice.

Objective: The intersection between immunology and metabolism contributes to the pathogenesis of obesity-associated metabolic diseases as well as molecular control of inflammatory responses. The metabolite itaconate and the cell-permeable derivatives have robust anti-inflammatory effects; therefore, it is hypothesized that cis-aconitate decarboxylase (Acod1)-produced itaconate has a protective, anti-inflammatory effect during diet-induced obesity and metabolic disease.

Methods: Wild-type and Acod1 mice were subjected to diet-induced obesity.

Prediction of cardiovascular events from systolic or diastolic blood pressure.

Over time, a focus on blood pressure has transferred from diastolic pressure to systolic pressure. Formal analyses of differences in predictive value are scarce. Our goal of the study was whether office SBP adds prognostic information to office DBP and whether both 24-h ambulatory SBP and 24-h ambulatory DBP is specifically important.

Serological Phenotyping Analysis Uncovers a Unique Metabolomic Pattern Associated With Early Onset of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a multifaceted disorder affecting epidemic proportion at global scope. Defective insulin secretion by pancreatic -cells and the inability of insulin-sensitive tissues to respond effectively to insulin are the underlying biology of T2DM. However, circulating biomarkers indicative of early diabetic onset at the asymptomatic stage have not been well described.

A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients.

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls.