The blood metabolome of cognitive function and brain health in middle-aged adults - influences of genes, gut microbiome, and exposome.

Increasing evidence suggests the involvement of metabolic alterations in neurological disorders, including Alzheimer's disease (AD), and highlights the significance of the peripheral metabolome, influenced by genetic factors and modifiable environmental exposures, for brain health. In this study, we examined 1,387 metabolites in plasma samples from 1,082 dementia-free middle-aged participants of the population-based Rotterdam Study. We assessed the relation of metabolites with general cognition (G-factor) and magnetic resonance imaging (MRI) markers using linear regression and estimated the variance of these metabolites explained by genes, gut microbiome, lifestyle factors, common clinical comorbidities, and medication using gradient boosting decision tree analysis.

Sequential STING and CD40 agonism drives massive expansion of tumor-specific T cells in liposomal peptide vaccines.

The clinical use of cancer vaccines is hampered by the low magnitude of induced T-cell responses and the need for repetitive antigen stimulation. Here, we demonstrate that liposomal formulations with incorporated STING agonists are optimally suited to deliver peptide antigens to dendritic cells in vivo and to activate dendritic cells in secondary lymphoid organs. One week after liposomal priming, systemic administration of peptides and a costimulatory agonistic CD40 antibody enables ultrarapid expansion of T cells, resulting in massive expansion of tumor-specific T cells in the peripheral blood two weeks after priming.

A Pooled Pharmacokinetic Analysis for Piperacillin/Tazobactam Across Different Patient Populations: From Premature Infants to the Elderly.

Background And Objectives: The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (f). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life.

Absence of Functional Autoantibodies Targeting Angiotensin II Type 1 Receptor (ATR) and Endothelin-1 Type A Receptor (ETR) in Circulation and Purified IgG from Patients with Systemic Sclerosis.

Objective: Systemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. While previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II type 1 receptor (ATR) and endothelin-1 type A receptor (ETR), leading to autoantibody-mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays.

NK cells-derived extracellular vesicles potency in the B cell lymphoma biotherapy.

Introduction: Extracellular vesicles of Natural Killer cells (NKEV) exert an antitumor effect towards hematopoietic and solid tumors and have an immune modulating effect, suggesting a promising role in immune and biotherapy. In this study, a continuation of our former works, we demonstrated a network by mass spectrometry analysis between NKEV protein cargo and antitumor effects. Human healthy NKEV, both exosomes and microvesicles, have a significant and direct cytotoxic effect against human B cell lymphoma in and conditions.

Intradermal versus subcutaneous immunization: Effects of administration route using a lipid-PLGA hybrid nanoparticle tuberculosis vaccine.

Tuberculosis (TB) remains a significant global health challenge, latently affecting around a quarter of the global population. The sole licensed TB vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), shows variable efficacy, particularly among adolescents and adults, underscoring the pressing need for more effective vaccination strategies. The administration route is crucial for vaccine efficacy, and administration via the skin, being rich in immune cells, may offer advantages over conventional subcutaneous routes, which lack direct access to abundant antigen-presenting cells.

The Hippo Pathway in Breast Cancer: The Extracellular Matrix and Hypoxia.

As one of the most prevalent malignant neoplasms among women globally, the optimization of therapeutic strategies for breast cancer has perpetually been a research hotspot. The tumor microenvironment (TME) is of paramount importance in the progression of breast cancer, among which the extracellular matrix (ECM) and hypoxia are two crucial factors. The alterations of these two factors are predominantly regulated by the Hippo signaling pathway, which promotes tumor invasiveness, metastasis, therapeutic resistance, and susceptibility.

Trajectories of biologic drug use before, during and after pregnancy: an Italian cohort study from the VALORE project.

Background: Monitoring biologic drug therapy during pregnancy in women with immune-mediated inflammatory diseases (IMIDs) is crucial to ensure treatments align with evidence-based practices.

Research Design And Methods: A retrospective cohort study based on healthcare claims data from eight Italian regions was conducted, analyzing deliveries between 2009 and 2021. The study included women receiving biologic drugs within nine months before their last menstruation.

Exploring the Fecal Metabolome in Infants With Cow's Milk Allergy: The Distinct Impacts of Cow's Milk Protein Tolerance Acquisition and of Synbiotic Supplementation.

Scope: Cow's milk allergy (CMA) is one of the most prevalent food allergies in early childhood, often treated via elimination diets including standard amino acid-based formula or amino acid-based formula supplemented with synbiotics (AAF or AAF-S). This work aimed to assess the effect of cow's milk (CM) tolerance acquisition and synbiotic (inulin, oligofructose, Bifidobacterium breve M-16 V) supplementation on the fecal metabolome in infants with IgE-mediated CMA.

Methods And Results: The CMA-allergic infants received AAF or AAF-S for a year during which fecal samples were collected.

Nutrient conditions affect antimicrobial pharmacodynamics in .

The infectious microenvironment in chronic respiratory tract infections is characterized by substantial variability in nutrient conditions, which may impact colonization and treatment response of pathogens. Metabolic adaptation of the cystic fibrosis (CF)-associated pathogen has been shown to lead to changes in antibiotic sensitivity. The impact of specific nutrients on the response to antibiotics is, however, poorly characterized.

Safety, Pharmacokinetics, and Pharmacodynamics of a First-in-Class ClC-1 Inhibitor to Enhance Muscle Excitability: Phase I Randomized Controlled Trial.

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human, randomized, double-blind, placebo-controlled study, which evaluated the safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects.

TMS and EEG Pharmacodynamic Effects of a Selective Sphingosine-1-Phosphate Subtype 1 Receptor Agonist on Cortical Excitability in Healthy Subjects.

Current anti-epileptic drugs lack efficacy, cause many side effects and one third of all patients are treatment-resistant. Drugs targeting the sphingosine-1-phosphate receptor show potential anti-convulsant effects in animal models and decrease cortical excitability in patients with multiple sclerosis, but available compounds alter lymphocyte trafficking and cause immunosuppression, limiting their clinical anti-epileptic potential. TRV045 is a selective sphingosine-1-phosphate subtype 1 receptor agonist without effects on lymphocyte trafficking, demonstrating efficacy in animal models of epilepsy, with the potential to target abnormal cortical excitability.

Gastrointestinal Conditions Affect Chronic Pain and Quality of Life in Women.

Pain is a chronic condition in many women; drugs used for its treatment are often accompanied by detrimental effects on many organs, including the gut. Once inflamed, the gut can affect pain processes. The aim of this study was to evaluate the general health of women suffering chronic pain, with particular attention to gastrointestinal (GI) conditions.

Interdependency of estradiol-mediated ERα activation and subsequent PR and GREB1 induction to control cell cycle progression.

Various groups of chemicals that we encounter in every-day life are known to disrupt the endocrine system, such as estrogen mimics that can disturb normal cellular development and homeostasis. To understand the effect of estrogen on intracellular protein dynamics and how this relates to cell proliferation, we aimed to develop a quantitative description of transcription factor complexes and their regulation of cell cycle progression in response to estrogenic stimulation. We designed a mathematical model that describes the dynamics of three proteins, GREB1, PR and TFF1, that are transcriptionally activated upon binding of 17β-estradiol (E2) to estrogen receptor alpha (ERα).

Elucidation on the In Vivo Activity of the Bivalent Opioid Peptide MACE2 against Several Types of Chronic Pain.

Biphalin is a bivalent μ/δ opioid receptor agonist showing a promising therapeutic profile with reduced side effects, but as a peptide is limited by poor metabolic stability and blood-brain barrier penetration. To improve these features, we developed the ligand and showed initial in vivo efficacy. To further explore the druggability of this ligand, in this report, we tested metabolic stability in human plasma, receptor engagement by 3 different routes of administration using the tail-flick test, and efficacy in 2 different pathological and chronic pain models.

Strategies for Using Postcolumn Infusion of Standards to Correct for Matrix Effect in LC-MS-Based Quantitative Metabolomics.

The matrix effect limits the accuracy of quantitation of the otherwise popular metabolomics technique liquid chromatography coupled to mass spectrometry (LC-MS). The gold standard to correct for this phenomenon, whereby compounds coeluting with the analyte of interest cause ionization enhancement or suppression, is to quantify an analyte based on the peak area ratio with an isotopologue added to the sample as an internal standard. However, these stable isotopes are expensive and sometimes unavailable.