A Cross Sectional Study of Cytokines in Women with Refractory Detrusor Overactivity versus Controls.

Introduction And Hypothesis: Previous work has suggested that refractory detrusor overactivity (DO) was commonly associated with urinary tract infection (UTI), which can lead to inflammatory changes in the bladder. This study aimed to investigate the concentrations of urinary cytokines in a large sample of women with refractory detrusor overactivity (DO) and age matched controls.

Methods: The urinary concentration of 27 cytokines in 140 women (95 with refractory DO and 45 age matched controls (women without urge incontinence)) was determined using the Human Cytokine 27-plex Assay.

Effect of pro-inflammatory cytokines on urothelial cell adenosine triphosphate release and breakdown.

Objectives: Urinary symptoms of urgency, frequency, and pain are thought to be the result of inflammation in several bladder pathologies although the cause of these symptoms remains uncertain. Extracellular adenosine triphosphate (ATP) released from the bladder urothelium during normal bladder stretch is believed to bind to purinergic receptors on afferent nerves to signal bladder sensation. This study examined pro-inflammatory cytokines in the urine of women with detrusor overactivity (DO) with or without urinary tract infection (UTI) compared to controls and then determined the effect of pro-inflammatory cytokines on ATP signaling (release and breakdown) from the urothelium.

Silica Nanoparticles Decorated with Ceria Quantum Dots Modulate Intra- and Extracellular Reactive Oxygen Species Formation and Selectively Reduce Human A375 Melanoma Cell Proliferation.

Nanomaterials show great promise for cancer treatment. Nonetheless, most nanomaterials lack selectivity for cancer cells, damaging healthy ones. Cerium dioxide (ceria, CeO) nanoparticles have been shown to exert selective toxicity toward cancer cells due to the redox modulating properties they display as their size decreases.

Effect of substituents on the ability of nickel Schiff base complexes with four pendant groups to bind to G-quadruplexes.

The synthesis of eleven new nickel Schiff base complexes each bearing four pendant groups is reported. The structures of the complexes differ in the identity of the pendant groups and/or diamine moiety. All complexes were characterised by microanalysis, Nuclear Magnetic Resonance (NMR) spectroscopy and Electrospray Ionisation Mass Spectrometry (ESI-MS), while the solid-state structures of two of the molecules were also determined using X-ray crystallographic methods.

Enhancing pancreatic cancer immunotherapy: Leveraging localized delivery strategies through the use of implantable devices and scaffolds.

Pancreatic cancer (PC) remains the predominant type of upper gastrointestinal tract cancer, associated with heightened morbidity and a survival rate below 12%. While immunotherapy has brought about transformative changes in the standards of care for most solid tumors, its application in PC is hindered by the ''cold tumor'' microenvironment, marked by the presence of immunosuppressive cells. Modest response rates in PC are attributed, in part to, the fibrotic stroma that obstructs the delivery of systemic immunotherapy.

Graft-versus-leukaemia immunity is retained following treatment with post-transplant cyclophosphamide alone or combined with tocilizumab in humanised mice.

Objectives: Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft-versus-leukaemia (GVL) immunity. However, this benefit is often mitigated by graft-versus-host disease (GVHD), which is reduced by post-transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity.

Post-Transplant Cyclophosphamide Combined with Brilliant Blue G Reduces Graft-versus-Host Disease without Compromising Graft-versus-Leukaemia Immunity in Humanised Mice.

Allogeneic haematopoietic stem cell transplantation (HSCT) leads to the establishment of graft-versus-leukaemia (GVL) immunity, but in many cases also results in the development of graft-versus-host disease (GVHD). This study aimed to determine if P2X7 antagonism using Brilliant Blue G (BBG) could improve the beneficial effects of post-transplant cyclophosphamide (PTCy) in a humanised mouse model of GVHD, without comprising GVL immunity. NOD.

Methods for studying P2X4 receptor ion channels in immune cells.

The P2X4 receptor is a trimeric ligand-gated ion channel activated by adenosine 5'-triphosphate (ATP). P2X4 is present in immune cells with emerging roles in inflammation and immunity, and related disorders. This review aims to provide an overview of the methods commonly used to study P2X4 in immune cells, focusing on those methods used to assess P2RX4 gene expression, the presence of the P2X4 protein, and P2X4 ion channel activity in these cells from humans, dogs, mice and rats.

Streptococcus 98.1 variants activate inflammatory caspases in human neutrophils.

CovRS, control of virulence regulatory system; GAS, Group A Streptococcus; PMN, polymorphonuclear leukocyte.

A Species-Specific Anti-Human P2X7 Monoclonal Antibody Reduces Graft-versus-Host Disease in Humanised Mice.

Graft-versus-host disease (GVHD) is a T cell-mediated inflammatory disorder that arises from allogeneic haematopoietic stem cell transplantation and is often fatal. The P2X7 receptor is an extracellular adenosine 5'-triphosphate-gated cation channel expressed on immune cells. Blockade of this receptor with small molecule inhibitors impairs GVHD in a humanised mouse model.

Low Pretreatment CD4:CD8 T Cell Ratios and CD39CD73CD19 B Cell Proportions Are Associated with Improved Relapse-Free Survival in Head and Neck Squamous Cell Carcinoma.

The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS).

Purinergic Signalling in Physiology and Pathophysiology.

Since its inception by the late Geoffrey Burnstock in the early 1970s [...

Tocilizumab increases regulatory T cells, reduces natural killer cells and delays graft-versus-host disease development in humanized mice treated with post-transplant cyclophosphamide.

Graft-versus-host disease (GVHD) is a life-threatening complication following donor hematopoietic stem cell transplantation, where donor T cells damage host tissues. This study investigated the effect of tocilizumab (TOC) combined with post-transplant cyclophosphamide (PTCy) on immune cell engraftment and GVHD development in a humanized mouse model. NOD-scid-IL2Rγ (NSG) mice were injected intraperitoneally with 2 × 10 human (h) peripheral blood mononuclear cells and cyclophosphamide (33 mg kg ) or saline on days 3 and 4, then TOC or control antibody (0.

Animal Models for the Investigation of P2X7 Receptors.

The P2X7 receptor is a trimeric ligand-gated cation channel activated by extracellular adenosine 5'-triphosphate. The study of animals has greatly advanced the investigation of P2X7 and helped to establish the numerous physiological and pathophysiological roles of this receptor in human health and disease. Following a short overview of the P2X7 distribution, roles and functional properties, this article discusses how animal models have contributed to the generation of P2X7-specific antibodies and nanobodies (including biologics), recombinant receptors and radioligands to study P2X7 as well as to the pharmacokinetic testing of P2X7 antagonists.

Multifunctional bismuth oxide (Bi O ) particles: Evidence for selective melanoma therapy.

The current study investigates the therapeutic and optical properties of bismuth oxide (Bi O ) particles for selective melanoma therapy and prevention. The Bi O particles were prepared using a standard precipitation method. The Bi O particles induced apoptosis in human A375 melanoma cells but not human HaCaT keratinocytes or CCD-1090Sk fibroblast cells.

Purinergic signalling in graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation is used to treat blood cancers, but often results in lethal graft-versus-host disease (GVHD). GVHD is an inflammatory disorder mediated by donor leukocytes that damage host tissues. Purinergic signalling plays important roles in GVHD development in mice but studies of these pathways in human GVHD remain limited.

P2X receptors: Insights from the study of the domestic dog.

Fifty years ago, the late Geoffrey Burnstock described the concept of purinergic nerves and transmission bringing into existence the broader concepts of purinergic signaling including P2X receptors. These receptors are trimeric ligand-gated cation channels activated by extracellular adenosine 5'-triphosphate (ATP). P2X receptors have important roles in health and disease and continue to gain interest as potential therapeutic targets in inflammatory, neurological, cardiovascular and many other disorders including cancer.

6-Furopyridine Hexamethylene Amiloride Is a Non-Selective P2X7 Receptor Antagonist.

P2X7 is an extracellular adenosine 5'-triphopshate (ATP)-gated cation channel present on leukocytes, where its activation induces pro-inflammatory cytokine release and ectodomain shedding of cell surface molecules. Human P2X7 can be partially inhibited by amiloride and its derivatives at micromolar concentrations. This study aimed to screen a library of compounds derived from amiloride or its derivative 5-(,-hexamethylene) amiloride (HMA) to identify a potential P2X7 antagonist.

Insights into mechanisms of graft-versus-host disease through humanised mouse models.

Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic haematopoietic stem cell transplantation (HSCT) for the treatment of haematological cancers and other blood-related disorders. GVHD is an inflammatory disorder, where the transplanted donor immune cells can mediate an immune response against the recipient and attack host tissues. Despite over 60 years of research, broad-range immune suppression is still used to prevent or treat GVHD, leading to an increased risk of cancer relapse and infection.

Humanized Mouse Model to Study the P2X7 Receptor in Graft-Versus-Host Disease.

Humanized mouse models of graft-versus-host disease (GVHD), where human immune cells are injected into immune deficient mice, are well established and provide opportunities to investigate pathways involved in GVHD development. This chapter provides an overview of human immune cell isolation, injection of these cells into immune deficient mice, monitoring of mice for signs of GVHD, and assessment of human cell engraftment using flow cytometry. Further, this chapter focuses on the P2X7 signaling pathway involved in GVHD, and describes a strategy to block the P2X7 receptor and examine the effect of this on GVHD development.

Preparation of the Murine Anti-Human P2X7 Receptor Monoclonal Antibody (Clone L4).

The murine anti-human P2X7 receptor monoclonal antibody (mAb) (clone L4) has been used to study the expression and function of the P2X7 receptor on primary leukocytes, keratinocytes, osteoblasts and neuronal cells, as well as various cell lines. This antibody has also been used to characterize polymorphic variants and isoforms of the P2RX7 gene and P2X7 site-directed mutations, and to identify molecules coassociated with P2X7 in the plasma membrane. This chapter describes the maintenance and cryopreservation of the L4 hybridoma cell line, as well as the generation of tissue culture supernatant containing the anti-human P2X7 mAb, and its subsequent purification by Protein A chromatography and conjugation to DyLight™ 488.