Cancer stem cells: Masters of all traits.

Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer.

Involvement of PAR-2 in the Induction of Cell-Specific Matrix Metalloproteinase-2 by Activated Protein C in Cutaneous Wound Healing.

We previously reported that human keratinocytes express protease-activated receptor (PAR)-2 and play an important role in activated protein C (APC)-induced cutaneous wound healing. This study investigated the involvement of PAR-2 in the production of gelatinolytic matrix metalloproteinases (MMP)-2 and -9 by APC during cutaneous wound healing. Full-thickness excisional wounds were made on the dorsum of male C57BL/6 mice.

Foxe1 Deletion in the Adult Mouse Is Associated With Increased Thyroidal Mast Cells and Hypothyroidism.

Context: Foxe1 is a key thyroid developmental transcription factor. Germline deletion results in athyreosis and congenital hypothyroidism. Some data suggest an ongoing role for maintaining thyroid differentiation.

Differential effects of radiation fractionation regimens on glioblastoma.

Background: Radiotherapy (RT) is a mainstay of treatment for patients with glioblastoma (GB). Early clinical trials show that short course hypofractionation showed no survival benefit compared to conventional regimens with or without temozolomide chemotherapy (TMZ) but reduces the number of doses required. Concerns around delayed neurological deficits and reduced cognition from short course hypofractionated RT remain a concern.

NF-κB regulation in maternal immunity during normal and IUGR pregnancies.

Intrauterine Growth Restriction (IUGR) is a leading cause of perinatal death with no effective cure, affecting 5-10% pregnancies globally. Suppressed pro-inflammatory Th1/Th17 immunity is necessary for pregnancy success. However, in IUGR, the inflammatory response is enhanced and there is a limited understanding of the mechanisms that lead to this abnormality.

Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas.

As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy.

Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma.

Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano).

Deficiency of protease-activated receptor (PAR) 1 and PAR2 exacerbates collagen-induced arthritis in mice via differing mechanisms.

Objectives: Protease-activated receptor (PAR) 1 and PAR2 have been implicated in RA, however their exact role is unclear. Here, we detailed the mechanistic impact of these receptors on the onset and development of inflammatory arthritis in murine CIA and antigen-induced arthritis (AIA) models.

Methods: CIA or AIA was induced in PAR1 or PAR2 gene knockout (KO) and matched wild type mice.

Are In Vitro Human Blood-Brain-Tumor-Barriers Suitable Replacements for In Vivo Models of Brain Permeability for Novel Therapeutics?

Background: High grade gliomas (HGG) are incapacitating and prematurely fatal diseases. To overcome the poor prognosis, novel therapies must overcome the selective and restricted permeability of the blood-brain barrier (BBB). This study critically evaluated whether in vitro human normal BBB and tumor BBB (BBTB) are suitable alternatives to "gold standard" in vivo models to determine brain permeability.

Overlooked potential of positrons in cancer therapy.

Positron (β) emitting radionuclides have been used for positron emission tomography (PET) imaging in diagnostic medicine since its development in the 1950s. Development of a fluorinated glucose analog, fluorodeoxyglucose, labelled with a β emitter fluorine-18 (F-FDG), made it possible to image cellular targets with high glycolytic metabolism. These targets include cancer cells based on increased aerobic metabolism due to the Warburg effect, and thus, F-FDG is a staple in nuclear medicine clinics globally.

Application of Mitochondrially Targeted Nanoconstructs to Neoadjuvant X-ray-Induced Photodynamic Therapy for Rectal Cancer.

In this work, we brought together two existing clinical techniques used in cancer treatment-X-ray radiation and photodynamic therapy (PDT), whose combination termed X-PDT uniquely allows PDT to be therapeutically effective in deep tissue. To this end, we developed mitochondrially targeted biodegradable polymer poly(lactic--glycolic acid) nanocarriers incorporating a photosensitizer verteporfin, ultrasmall (2-5 nm) gold nanoparticles as radiation enhancers, and triphenylphosphonium acting as the mitochondrial targeting moiety. The average size of the nanocarriers was about 160 nm.

Temporal and spatial modulation of the tumor and systemic immune response in the murine Gl261 glioma model.

Glioblastoma, the most aggressive form of glioma, has a 5-year survival rate of <5%. While radiation and immunotherapies are routinely studied in the murine Gl261 glioma model, little is known about its inherent immune response. This study quantifies the temporal and spatial localization of immune cell populations and mediators during glioma development.

Sub-acute Toxicity in Non-cancerous Tissue and Immune-Related Adverse Events of a Novel Combination Therapy for Cancer.

Brain, lung, and colon tissue experience deleterious immune-related adverse events when immune-oncological agents or radiation are administered. However, there is a paucity of information regarding whether the addition of radiation to immuno-oncological regimens exacerbates the tissue inflammatory response. We used a murine model to evaluate sub-acute tissue damage and the systemic immune response in C57Bl/6 mice when administered systemic anti-programmed cell death protein 1 (αPD-1) immunotherapy alone or in combination with stereotactic fractionated 10 gray/5 X-ray radiation to normal brain, lung or colon tissue.

Activated protein C targets immune cells and rheumatoid synovial fibroblasts to prevent inflammatory arthritis in mice.

Objectives: To investigate whether activated protein C (APC), a physiological anticoagulant can inhibit the inflammatory/invasive properties of immune cells and rheumatoid arthritis synovial fibroblasts (RASFs) in vitro and prevent inflammatory arthritis in murine antigen-induced arthritis (AIA) and CIA models.

Methods: RASFs isolated from synovial tissues of patients with RA, human peripheral blood mononuclear cells (PBMCs) and mouse thymus cells were treated with APC or TNF-α/IL-17 and the following assays were performed: RASF proliferation and invasion by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell invasion assays, respectively; cytokines and signalling molecules using ELISA or western blot; Th1 and Th17 phenotypes in human PBMCs or mouse thymus cells by flow cytometry. The in vivo effect of APC was evaluated in AIA and CIA models.

Radiation, inflammation and the immune response in cancer.

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences.

Co-expression of CD21L and IL17A defines a subset of rheumatoid synovia, characterised by large lymphoid aggregates and high inflammation.

Objective: To determine whether the expression of IL17A and CD21L genes in inflamed rheumatoid synovia is associated with the neogenesis of ectopic lymphoid follicle-like structures (ELS), and if this aids the stratification of rheumatoid inflammation and thereby distinguishes patients with rheumatoid arthritis that might be responsive to specific targeted biologic therapies.

Methods: Expression of IL17A and CD21L genes was assessed by RT-PCR, qRT-PCR and dPCR in synovia from 54 patients with rheumatoid arthritis. A subset of synovia (n = 30) was assessed by immunohistology for the presence of CD20+ B-lymphocytes and size of CD20+ B-lymphocyte aggregates as indicated by maximum radial cell count.

The intertwined fates of inflammation and coagulation in glioma.

Inflammation and coagulation are two intertwined pathways with evolutionary ties being traced back to the hemocyte, a single cell type in invertebrates that has functions in both the inflammatory and coagulation pathways. These systems have functioned together throughout evolution to provide a solid defence against infection, damaged cells and irritants. While these systems work in harmony the majority of the time, they can also become dysregulated or corrupted by tumours, enhancing tumour proliferation, invasion, dissemination and survival.

Formyl peptide receptor-2 is decreased in foetal growth restriction and contributes to placental dysfunction.

Study Question: What is the association between placental formyl peptide receptor 2 (FPR2) and trophoblast and endothelial functions in pregnancies affected by foetal growth restriction (FGR)?

Summary Answer: Reduced FPR2 placental expression in idiopathic FGR results in significantly altered trophoblast differentiation and endothelial function in vitro.

What Is Known Already: FGR is associated with placental insufficiency, where defective trophoblast and endothelial functions contribute to reduced feto-placental growth.

Study Design, Size, Duration: The expression of FPR2 in placental tissues from human pregnancies complicated with FGR was compared to that in gestation-matched uncomplicated control pregnancies (n = 25 from each group).

Inflammatory and Immune System Markers.

Since preeclampsia was first described by Hippocrates in 400 BC, the theory of its causation has shifted from toxins to a current theory that incorporates both vascular and immunological causation. Poor placentation whether it is genetically predisposed or due to low expression of defective HLA-G on fetal trophoblasts is believed to be the initial insult. Oxidative stress from placental ischemia/hypoxia leads to an overload of trophoblast debris by stimulating apoptosis or necrosis.

Embryonic/fetal mortality and intrauterine growth restriction is not exclusive to the CBA/J sub-strain in the CBA × DBA model.

Inbred strains of mice are powerful models for understanding human pregnancy complications. For example, the exclusive mating of CBA/J females to DBA/2J males increases fetal resorption to 20-35% with an associated decline in placentation and maintenance of maternal Th1 immunity. More recently other complications of pregnancy, IUGR and preeclampsia, have been reported in this model.

Aberrant levels of natural IgM antibodies in osteoarthritis and rheumatoid arthritis patients in comparison to healthy controls.

Natural IgM antibodies (nIgM) are polyreactive autoantibodies that have diverse roles in regulating autoimmunity, systemic inflammation and removal of oxidized low-density lipoproteins (oxLDL). We hypothesized that aberrant states of nIgM may exist in persons with osteoarthritis (OA) and rheumatoid arthritis (RA). Herein, we characterized and compared the levels of nIgM specific for phosphorylcholine (anti-PC), double-stranded DNA (anti-dsDNA), and galactosyl (anti-Gal) in persons with OA, RA and healthy controls (HC).

Exosomes: Mechanisms of Uptake.

Exosomes are 30-100 nm microvesicles which contain complex cellular signals of RNA, protein and lipids. Because of this, exosomes are implicated as having limitless therapeutic potential for the treatment of cancer, pregnancy complications, infections, and autoimmune diseases. To date we know a considerable amount about exosome biogenesis and secretion, but there is a paucity of data regarding the uptake of exosomes by immune and non-immune cell types (e.

Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradation.

Objective: The aim of this study was to investigate the effect of endogenous matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) on the invasive characteristics of RA synovial fibroblasts.

Methods: Synovial fibroblasts isolated from patients with RA or OA were treated with MMP small interfering RNA (siRNA), inhibitors and recombinant proteins or TNF-α, with or without cartilage explants. Cell viability and proliferation were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and 5-bromo-2-deoxyuridine (BrdU) proliferation assays, respectively; apoptosis by an in situ cell death detection kit; migration and invasion by CytoSelect invasion assay, scratch migration and collagen gel assays; cartilage degradation by 1,9-dimethylmethylene blue assay; and inflammatory mediators and MMPs by ELISA, western blot and zymography.

Activated protein C: A regulator of human skin epidermal keratinocyte function.

Activated protein C (APC) is a physiological anticoagulant, derived from its precursor protein C (PC). Independent of its anticoagulation, APC possesses strong anti-inflammatory, anti-apoptotic and barrier protective properties which appear to be protective in a number of disorders including chronic wound healing. The epidermis is the outermost skin layer and provides the first line of defence against the external environment.

Endothelial protein C receptor-associated invasiveness of rheumatoid synovial fibroblasts is likely driven by group V secretory phospholipase A2.

Introduction: Rheumatoid synovial fibroblasts (RASFs) mediate joint inflammation and destruction in rheumatoid arthritis (RA). Endothelial protein C receptor (EPCR) is a specific receptor for the natural anticoagulant activated protein C (APC). It mediates the cytoprotective properties of APC and is expressed in rheumatoid synovial tissue.