PAF-R on activated T cells: Role in the IL-23/Th17 pathway and relevance to multiple sclerosis.

IL-23 is a potent stimulus for Th17 cells. These cells have a distinct developmental pathway from Th1 cells induced by IL-12 and are implicated in autoimmune and inflammatory disorders including multiple sclerosis (MS). TGF-β, IL-6, and IL-1, the transcriptional regulator RORγt (RORC) and IL-23 are implicated in Th17 development and maintenance.

Granulocyte-macrophage colony stimulatory factor enhances the pro-inflammatory response of interferon-γ-treated macrophages to Pseudomonas aeruginosa infection.

Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ventilation or recurrent infections, particularly in cystic fibrosis (CF) patients. CF patients have been proposed to have a Th2 and Th17-biased immune response suggesting that the lack of Th1 and/or over exuberant Th17 responses could contribute to the establishment of chronic P. aeruginosa infection and deterioration of lung function.

DNA content analysis of colorectal cancer defines a distinct 'microsatellite and chromosome stable' group but does not predict response to radiotherapy.

Colorectal cancers (CRC) are thought to have genetic instability in the form of either microsatellite instability (MSI) or chromosomal instability (CIN). Recently, tumours have been described without either MSI or CIN, that is, microsatellite and chromosome stable (MACS) CRCs. We investigated the (i) frequency of the MACS-CRCs and (ii) whether this genotype predicted responsiveness to neoadjuvant chemoradiotherapy.

Circulating antibody and memory B-Cell responses to C. difficile toxins A and B in patients with C. difficile-associated diarrhoea, inflammatory bowel disease and cystic fibrosis.

C. difficile infection (CDI) is rarely reported in cystic fibrosis (CF) patients despite frequent hospitalisations and antibiotic usage. Conversely, the prevalence of CDI in inflammatory bowel disease (IBD) has received increased attention.

Abnormal T regulatory cells (Tregs: FOXP3+, CTLA-4+), myeloid-derived suppressor cells (MDSCs: monocytic, granulocytic) and polarised T helper cell profiles (Th1, Th2, Th17) in women with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC) and surgery: failure of abolition of abnormal treg profile with treatment and correlation of treg levels with pathological response to NAC.

Background: Host defences play a key role in tumour growth. Some of the benefits of chemotherapy may occur through modulation of these defences. The aim of this study was to define the status of regulatory cells in women with large and locally advanced breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery.

The effect of fenoldopam and dopexamine on cytokine and endotoxin release following on-pump coronary artery bypass grafting: a prospective randomized double-blind trial.

Background: Surgical trauma, exposure to an external circuit, and reduced organ perfusion contribute to the systemic inflammatory response following cardiopulmonary bypass (CPB). Reduced splanchnic perfusion causes disruption of the gastrointestinal mucosal barrier and the release of endotoxins. Fenoldopam (a new dopamine 1 receptor agonist) has been shown to be a specific renosplanchnic vasodilator in animal and human studies.

Effect of increased pump flow on hepatic blood flow and systemic inflammatory response following on-pump coronary artery bypass grafting.

Unlabelled: Reduced organ perfusion during cardiopulmonary bypass (CPB) is responsible for morbidity associated with cardiac surgery. Non-pulsatile flow and hypothermia during CPB have been shown to cause reduced perfusion. During CPB, cardiac output is directly proportional to the pump flow rate.

The stem cell marker CD133 associates with enhanced colony formation and cell motility in colorectal cancer.

CD133 is a membrane molecule that has been, controversially, reported as a CSC marker in colorectal cancer (CRC). In this study, we sought to clarify the expression and role of CD133 in CRC. Initially the size of the CD133-expressing (CD133+) population in eight well-described CRC cell lines was measured by flow cytometry and was found to range from 0% to >95%.

Regulation in chronic obstructive pulmonary disease: the role of regulatory T-cells and Th17 cells.

COPD (chronic obstructive pulmonary disease) is an inflammatory disorder of the airways, which is associated with irreversible airway obstruction. The pathological hallmarks of COPD are destruction of the lung parenchyma (pulmonary emphysema), inflammation of the central airways (chronic bronchitis) and inflammation of the peripheral airways (respiratory bronchiolitis). Tobacco smoking is established as the main aetiological factor for COPD.

CD24 is upregulated in inflammatory bowel disease and stimulates cell motility and colony formation.

Background: We investigated whether CD24 (reportedly a stem cell marker and adhesion molecule) was expressed in regenerative mucosa in inflammatory bowel disease (IBD) and whether it could be functionally relevant.

Methods: CD24 expression was examined in 10 cases of IBD and the relationship of CD24 with Wnt signaling was tested using dominant negative (DN)-TCF4 expression. For functional evaluation, CD24 was 1) cloned and forcibly expressed in HCT116 (which expresses very low levels of CD24) and 2) knocked-down by RNA interference in HT29 (which expresses high levels of CD24).

Expression of activity-dependent neuroprotective protein in the immune system: possible functions and relevance to multiple sclerosis.

Background: Activity-dependent neuroprotector (ADNP) is a neuroprotective molecule containing an 8-amino acid peptide, NAPVSIPQ (NAP), that is sufficient for its neuroprotective effects.

Objective: To assess the expression of ADNP in the human immune system in normal subjects and multiple sclerosis patients. MaterialsandMethods: ADNP expression was assessed in peripheral blood mononuclear cells (PBMCs) from healthy donors and multiple sclerosis (MS) patients using staining with anti-ADNP (NAP) antibodies and markers for T cells, B cells, monocytes and natural killer cells.

The effect of fenoldopam and dopexamine on hepatic blood flow and hepatic function following coronary artery bypass grafting with hypothermic cardiopulmonary bypass.

Background: Hypothermic cardiopulmonary bypass is associated with low perfusion state causing a mismatch between demand and supply to various organs such as gut, kidneys and brain. The consequences are thought to be responsible for postoperative complications like systemic inflammatory response, renal failure, neurological injury, etc. Pharmacological agents like dopamine, dopexamine and dobutamine have been used in an attempt to reduce hypoperfusion and hence complications.

Allergen-driven suppression of thiol production by human dendritic cells and the effect of thiols on T cell function.

Dendritic cells are a major source of extracellular thiols needed for T cell activation, a process in which CD40-mediated stimulation plays a pivotal role. The Dermatophagoides pteronyssinus group 1 mite allergen (Der p 1) has previously been shown to cleave CD40 from the surface of human dendritic cells, thereby suggesting that Der p 1 might compromise the ability of these cells to sustain thiol production during T cell activation. This has therefore prompted us to examine the effect of the mite protease allergen Der p 1 on thiol production by human dendritic cells.

Significant immunomodulatory effects of Pseudomonas aeruginosa quorum-sensing signal molecules: possible link in human sepsis.

Pathogenic bacteria use quorum-sensing signal molecules to co-ordinate the expression of virulence genes. Animal-based studies have demonstrated the immunomodulatory effects of quorum-sensing signal molecules. In the present study, we have examined the impact of these molecules on normal human immune function in vitro and compared this with immune changes in patients with sepsis where quorum-sensing signal molecules were detected in the sera of patients.

Curcumin modulation of IFN-beta and IL-12 signalling and cytokine induction in human T cells.

Curcumin is a polyphenol derived from the dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties. Curcumin has been shown to exhibit an inhibitory effect on the production of inflammatory cytokines by human monocytes and has inhibited the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in association with a decrease in interleukin 12 (IL-12) production and signal transducer and activator of transcription 4 (STAT4) activation.

Reciprocal effects of IFN-beta and IL-12 on STAT4 activation and cytokine induction in T cells.

IL-12 is an immunoregulatory cytokine, which promotes Th1 cell differentiation and is a major inducer of IFN-gamma. IFN-beta, a Type I IFN used in the treatment of multiple sclerosis, has been shown to significantly increase the expression of the anti-inflammatory cytokine IL-10, a major suppressor of Th1 cytokines. The beneficial immunomodulatory effects of IFN-beta may in part be a result of its ability to suppress IL-12.

Effects of glucocorticoids on STAT4 activation in human T cells are stimulus-dependent.

Glucocorticoids affect the immune system by a number of mechanisms, including modulation of cytokine production in lymphocytes. Glucocorticoids suppress T helper cell type 1 immune responses by decreasing the ability of T cells to respond to interleukin (IL)-12, a major inducer of interferon (IFN)-gamma. IFN-beta increases the expression of the anti-inflammatory cytokine IL-10 and suppresses IL-12.

HIV coreceptor and chemokine ligand gene expression in the male urethra and female cervix.

Objective: Isolates with a tropism for the coreceptor CCR5 are the predominant viral strain transmitted following heterosexual transmission. We have investigated coreceptor expression levels within male and female genital epithelia to assess whether selective transmission can be explained by elevated CCR5 expression within the genital epithelia per se.

Design: Individuals attending a local genitourinary medicine unit were recruited, and samples of genital epithelia obtained using either a cytobrush (females) or urethral swab (males).

T-cell-stimulating protein A elicits immune responses during meningococcal carriage and human disease.

In recognition of the need for immunological memory-inducing components for future Neisseria meningitidis group B vaccines, we previously searched the proteome of N. meningitidis and identified T-cell-stimulating protein A (TspA). This study was designed to confirm the immunogencity of TspA and to examine the subset of T-helper cell responses to the protein in patients and nasopharyngeal carriers.

Dendritic cells are dysfunctional in patients with operable breast cancer.

Background: Dendritic cells (DCs) play a crucial role in presenting antigens to T lymphocytes and inducing cytotoxic T cells. DCs have been studied in patients with breast cancer to define the factors leading to failure of an effective systemic and locoregional anticancer host response.

Methods: Purified DCs were obtained from peripheral blood (PB) and lymph nodes (LNs) of women with operable breast cancer, using immunomagnetic bead selection.

Colorectal cancer cells induce lymphocyte apoptosis by an endothelial monocyte-activating polypeptide-II-dependent mechanism.

Endothelial monocyte-activating polypeptide-II (EMAP-II) was first isolated from cell growth medium conditioned by tumor cells, and is closely related or identical with the p43 component of the mammalian multisynthase complex. In its secreted form, EMAP-II has multiple cytokine-like activities in vitro, inducing procoagulant activity on the surface of endothelial cells, increasing expression of E- and P-selectins and TNF-R1, and directing migration of monocytes and neutrophils. EMAP-II has also been shown to induce apoptosis in endothelial cells, leading to the suggestion that it is a proinflammatory polypeptide with antiangiogenic activity.

Cell cycle- and age-dependent activation of Sod1p drives the formation of stress resistant cell subpopulations within clonal yeast cultures.

Phenotypic heterogeneity describes non-genetic variation that exists between individual cells within isogenic populations. The basis for such heterogeneity is not well understood, but it is evident in a wide range of cellular functions and phenotypes and may be fundamental to the fitness of microorganisms. Here we use a suite of novel assays applied to yeast, to provide an explanation for the classic example of heterogeneous resistance to stress (copper).

Smooth and rough lipopolysaccharide phenotypes of Brucella induce different intracellular trafficking and cytokine/chemokine release in human monocytes.

Virulence of the intracellular pathogen Brucella for humans is mainly associated with its lipopolysaccharide (LPS) phenotype, with smooth LPS phenotypes generally being virulent and rough ones not. The reason for this association is not quite understood. We now demonstrate by flow cytometry, electron microscopy, and ELISA that human peripheral blood monocytes interact both quantitatively and qualitatively different with smooth and rough Brucella organisms in vitro.

Antitumor polycyclic acridines. Part 12. Physical and biological properties of 8,13-diethyl-6-methylquino[4,3,2-kl]acridinium iodide: a lead compound in anticancer drug design.

The biophysical and biological characterization of 8,13-diethyl-6-methylquino[4,3,2-k]lacridinium iodide (6) is reported. The compound binds to DNA, as measured by UV, fluorescence, and circular dichroism studies, and stabilizes the double helix and higher order DNA structures (DNA triplexes and quadruplexes) against thermal denaturation. Unlike many DNA ligands, (6) shows no specificity for binding to specific base pair combinations and does not inhibit topoisomerase I (topo I) or topo II activity.