The Tumorigenicity of Breast Cancer Cells Is Reduced upon Treatment with Small Extracellular Vesicles Isolated from Heparin Treated Cell Cultures.

As a member of the HPSG family, heparin is often used as a specific probe of their role in cell physiology; indeed, we have previously shown a reduction in the tumorigenicity of breast cancer cells when cultured in its presence. However, a partial reversal of the anti-tumorigenic effect occurred when the treated cells were cultured in fresh medium without heparin, which led us to consider whether a more persistent effect could be achieved by treatment of the cells with small extracellular vesicles (sEV) from heparin-treated cells. The tumorigenicity was analyzed using sEV isolated from the culture medium of heparin-treated MCF-7 and MDA-MB231 breast cancer cells (sEV-HT) or from conditioned medium following the termination of treatment (heparin discontinued, sEV-HD).

The development and preliminary evaluation of a clinician e-learning training platform for a neonatal sepsis risk monitor for use in ICU settings.

Background: Training clinicians on the use of hospital-based patient monitoring systems (PMS) is vital to mitigate the risk of use errors and of frustration using these devices, especially when used in ICU settings. PMS training is typically delivered through face-to-face training sessions in the hospital. However, it is not always feasible to deliver training in this format to all clinical staff given some constraints (e.

Fresh and Cryopreserved Human Umbilical-Cord-Derived Mesenchymal Stromal Cells Attenuate Injury and Enhance Resolution and Repair following Ventilation-Induced Lung Injury.

Background: Ventilator-induced lung injury (VILI) frequently worsens acute respiratory distress syndrome (ARDS) severity. Human mesenchymal stem/stromal cells (MSCs) offer considerable therapeutic promise, but the key impediments of clinical translation stem from limitations due to cell source and availability, and concerns regarding the loss of efficacy following cryopreservation. These experiments compared the efficacy of umbilical-cord-derived MSCs (UC-MSCs), a readily available and homogenous tissue source, to the previously more widely utilised bone-marrow-derived MSCs (BM-MSCs).

Augmenting Critical Care Patient Monitoring Using Wearable Technology: Review of Usability and Human Factors.

Background: Continuous monitoring of the vital signs of critical care patients is an essential component of critical care medicine. For this task, clinicians use a patient monitor (PM), which conveys patient vital sign data through a screen and an auditory alarm system. Some limitations with PMs have been identified in the literature, such as the need for visual contact with the PM screen, which could result in reduced focus on the patient in specific scenarios, and the amount of noise generated by the PM alarm system.

Umbilical Cord-Derived CD362 Mesenchymal Stromal Cells Attenuate Polymicrobial Sepsis Induced by Caecal Ligation and Puncture.

Mesenchymal stromal cells (MSCs) have a multimodal, immunomodulatory mechanism of action and are now in clinical trials for single organ and systemic sepsis. However, a number of practicalities around source, homogeneity and therapeutic window remain to be determined. Here, we utilised conditioned medium from CD362-sorted umbilical cord-human MSCs (UC-hMSCs) for a series of in vitro anti-inflammatory assays and the cryopreserved MSCs themselves in a severe (Series 1) or moderate (Series 2+3) caecal ligation and puncture (CLP) rodent model.

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin.

Novel Interface Designs for Patient Monitoring Applications in Critical Care Medicine: Human Factors Review.

Background: The patient monitor (PM) is one of the most commonly used medical devices in hospitals worldwide. PMs are used to monitor patients' vital signs in a wide variety of patient care settings, especially in critical care settings, such as intensive care units. An interesting observation is that the design of PMs has not significantly changed over the past 2 decades, with the layout and structure of PMs more or less unchanged, with incremental changes in design being made rather than transformational changes.

Cytokine pre-activation of cryopreserved xenogeneic-free human mesenchymal stromal cells enhances resolution and repair following ventilator-induced lung injury potentially via a KGF-dependent mechanism.

Background: Human mesenchymal stem/stromal cells (hMSCs) represent a promising therapeutic strategy for ventilator-induced lung injury (VILI) and acute respiratory distress syndrome. Translational challenges include restoring hMSC efficacy following cryopreservation, developing effective xenogeneic-free (XF) hMSCs and establishing true therapeutic potential at a clinically relevant time point of administration. We wished to determine whether cytokine pre-activation of cryopreserved, bone marrow-derived XF-hMSCs would enhance their capacity to facilitate injury resolution following VILI and elucidate mechanisms of action.

Human Mesenchymal Stem Cell Secretome from Bone Marrow or Adipose-Derived Tissue Sources for Treatment of Hypoxia-Induced Pulmonary Epithelial Injury.

Unlabelled: Alveolar epithelial dysfunction induced by hypoxic stress plays a significant role in the pathological process of lung ischemia-reperfusion injury (IRI). Mesenchymal stem cell (MSC) therapies have demonstrated efficacy in exerting protective immunomodulatory effects, thereby reducing airway inflammation in several pulmonary diseases.

Aim: This study assesses the protective effects of MSC secretome from different cell sources, human bone marrow (BMSC) and adipose tissue (ADSC), in attenuating hypoxia-induced cellular stress and inflammation in pulmonary epithelial cells.

Total Artificial Heart Implantation as a Bridge to Heart Transplantation in an Active Duty Service Member With Amyloid Cardiomyopathy.

Introduction: Cardiac involvement by light-chain (AL) amyloid occurs in up to 50% of patients with primary AL amyloidosis. The prognosis of amyloid heart disease is poor with 1-year survival rates of 35 to 40%. Historically, heart transplantation was considered controversial for patients with AL amyloid cardiomyopathy (CM) given the systemic nature of the disease and poor survival.

Epitope-dependent mechanisms of CD27 neutralization revealed by X-ray crystallography.

CD27 is a T and B cell co-stimulatory protein of the TNF receptor superfamily dependent on the availability of the TNF-like ligand CD70. Two anti-CD27 neutralizing monoclonal antibodies were obtained from mouse hybridoma and subsequently humanized and optimized for binding the target. The two antibodies are similar in terms of their CD27-binding affinity and ability to block NF-κB signaling, however their clearance rates in monkeys are very different.

Hypercapnic acidosis attenuates pulmonary epithelial stretch-induced injury via inhibition of the canonical NF-κB pathway.

Background: Hypercapnia, with its associated acidosis (HCA), is a consequence of respiratory failure and is also seen in critically ill patients managed with conventional "protective" ventilation strategies. Nuclear factor kappa-B (NF-κB), a pivotal transcription factor, is activated in the setting of injury and repair and is central to innate immunity. We have previously established that HCA protects against ventilation-induced lung injury in vivo, potentially via a mechanism involving inhibition of NF-κB signaling.

Binding and inhibition of drug transport proteins by heparin: a potential drug transporter modulator capable of reducing multidrug resistance in human cancer cells.

A major problem in cancer treatment is the development of resistance to chemotherapeutic agents, multidrug resistance (MDR), associated with increased activity of transmembrane drug transporter proteins which impair cytotoxic treatment by rapidly removing the drugs from the targeted cells. Previously, it has been shown that heparin treatment of cancer patients undergoing chemotherapy increases survival. In order to determine whether heparin is capable reducing MDR and increasing the potency of chemotherapeutic drugs, the cytoxicity of a number of agents toward four cancer cell lines (a human enriched breast cancer stem cell line, two human breast cancer cell lines, MCF-7 and MDA-MB-231, and a human lung cancer cell line A549) was tested in the presence or absence of heparin.

Perturbation of the heparin/heparin-sulfate interactome of human breast cancer cells modulates pro-tumourigenic effects associated with PI3K/Akt and MAPK/ERK signalling.

Heparansulfate-proteoglycans (HSPGs) interact via their polyanionic heparansulfate (HS) side chains with a variety of proteins on the cell surface or within the extracellular matrix membrane. The large number of heparin/HS binding proteins form a highly interconnected functional network, which has been termed as the heparin/HS interactome and is functionally linked to physiological and pathological processes. The aim of this study was to investigate the global effect of these protein-HSPG interactions on the tumourigenicity of two breast cancer cell lines (MCF-7 and MDA-MB-231).

Protective role of cyclooxygenase (COX)-2 in experimental lung injury: evidence of a lipoxin A4-mediated effect.

Background: Polymorphoneutrophils (PMNs) are activated by inflammatory mediators following splanchnic ischemia/reperfusion (I/R), potentially injuring organs such as the lung. As a result, some patients develop respiratory failure following abdominal aortic aneurysm repair. Pulmonary cyclooxygenase (COX)-2 protects against acid aspiration and bacterial instillation via lipoxins, a family of potent anti-inflammatory lipid mediators.

A novel EPO receptor agonist improves glucose tolerance via glucose uptake in skeletal muscle in a mouse model of diabetes.

Patients treated with recombinant human Epo demonstrate an improvement in insulin sensitivity. We aimed to investigate whether CNTO 530, a novel Epo receptor agonist, could affect glucose tolerance and insulin sensitivity. A single administration of CNTO 530 significantly and dose-dependently reduced the area under the curve in a glucose tolerance test in diet-induced obese and diabetic mice after 14, 21, and 28 days.

Protocol based on thromboelastograph (TEG) out-performs physician preference using laboratory coagulation tests to guide blood replacement during and after cardiac surgery: a pilot study.

Background: Allogenic blood transfusion may affect clinical outcomes negatively. Up to 20% of blood transfusions in the United States are associated with cardiac surgery and so strategies to conserve usage are of importance. This study compares administration according to physician's choice based on laboratory coagulation tests with application of a strict protocol based on the thromboelastograph (TEG).

Protein engineering strategies for sustained glucagon-like peptide-1 receptor-dependent control of glucose homeostasis.

Objective: We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform.

Inhibition of airway smooth muscle adhesion and migration by the disintegrin domain of ADAM-15.

Disintegrin and metalloprotease proteins (ADAMs) are membrane-anchored glycoproteins involved in cell adhesion, cell fusion, protein ecto-domain shedding, and intracellular signaling. We examined whether the disintegrin domain of ADAM-15 (named ddADAM-15) containing an Asp-Gly-Asp (RGD) integrin-binding motif could interfere with airway smooth muscle cell (ASMC) adhesion and migration. Recombinant ddADAM-15 adhered to human ASMCs with saturation kinetics, and was beta(1)-integrin dependent.

The role of anticoagulation in cancer patients: facts and figures.

Thromboembolic events contribute significantly to the morbidity and mortality in cancer. Effective and safe anticoagulation - mainstay in prevention and treatment of thrombosis - remains very challenging clinical task in oncology patients - population of high rate of treatment failure, bleeding complications and thromboembolic events recurrences. Prospective randomized clinical studies have documented that with advent of low molecular weight heparins new possibilities for thrombosis treatment and long-term prevention with more convenient and safe anticoagulation have emerged.

Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumour suppression.

Aims: The use of doxorubicin (DOX) as a chemotherapeutic agent is limited by cardiac injury. Iloprost, a stable synthetic analogue of prostacyclin, has previously been shown to protect against DOX-induced cardiomyocyte injury in vitro. Here, we addressed whether iloprost is cardioprotective in vivo and whether it compromises the anti-tumour efficacy of DOX.

Characterization of antibodies to CA 125 that bind preferentially to the cell-associated form of the antigen.

Objective: Antibodies to CA 125 have been used to predict relapse of ovarian cancer, but have performed poorly as therapeutic agents. One rationale for this is antibody binding to circulating shed antigen. Our aim in this study was to develop antibodies to human CA 125 that have enhanced selectivity for the cell-associated form of the antigen.

Pharmacokinetics, biodistribution, and radioimmunotherapy with monoclonal antibody 776.1 in a murine model of human ovarian cancer.

776.1 is a murine IgG1 monoclonal antibody to the human ovarian cancer antigen CA 125 that has the unique property of having a clear preference for binding to the cell-associated form of the antigen. We have examined the tumor localization properties and efficacy of 776.