Innate effector cells in angiogenesis and lymphangiogenesis

Angiogenesis and lymphangiogenesis are distinct and complex processes requiring a finely tuned balance between stimulatory and inhibitory signals. During adulthood, angiogenesis and lymphangiogenesis are activated at sites of tumor growth, tissue injury and remodeling, and chronic inflammation. Vascular endothelial growth factors (VEGFs), angiopoietin (ANGPTs) and a multitude of additional signaling molecules play distinct roles in the modulation of angiogenesis/lymphangiogenesis. VEGFs and ANGPTs activate specific tyrosine kinase receptor (e.g., VEGFR1, VEGFR-2, VEGFR-3 and TIE2 respectively), expressed on blood endothelial cells (angiogenesis) and lymphatic endothelial cells (lymphangiogenesis). Although tumor cells produce VEGFs and other proangiogenic mediators, tissue resident (e.g., macrophages, mast cells) and circulating immune cells (e.g., basophils, neutrophils, monocytes, eosinophils) are an important source of angiogenic/lymphangiogenic mediators in inflammation and in tumor microenvironment and at site of chronic inflammation. Certain immune cells can also release anti-angiogenic factors. Mast cells, basophils, neutrophils and presumably other immune cells are not only a source of angiogenic/lymphangiogenic molecules, but also their target. Cells of the immune system need consideration as major players and possible targets for therapeutic manipulation of angiogenesis/lymphangiogenesis in chronic inflammatory disorders and tumors

Diffraction dissociation in proton-proton collisions at s\sqrt{s} = 0.9 TeV, 2.76 TeV and 7 TeV with ALICE at the LHC

The relative rates of single- and double- diffractive processes were measured with the ALICE detector by studying properties of gaps in the pseudorapidity distribution of particles produced in proton-proton collisions at $\sqrt{s}$ = 0.9 TeV, 2.76 TeV and 7 TeV. ALICE triggering efficiencies are determined for various classes of events, using a detector simulation validated with data on inclusive particle production. Cross-sections are determined using van der Meer scans to measure beam properties and obtain a measurement of the luminosity

Endovascular Treatment of a Ruptured Pararenal Abdominal Aortic Aneurysm in a Patient With Coronavirus Disease-2019: Suggestions and Case Report

The aim of this report is to discuss emergent repair for complex aortic diseases in patients affected by novel coronavirus pneumonia (coronavirus disease-2019 [COVID-19]), describing a case of ruptured pararenal aortic aneurysm. An eighty-year-old man with COVID-19 was admitted for ruptured aneurysm of the pararenal aorta and hemorrhagic shock. Endovascular repair was chosen, and a proximal extension of the previous abdominal endograft was performed with parallel stents in the right renal artery and the superior mesenteric artery. Endovascular treatment and early anticoagulation are the key for success for vascular emergencies in patients with COVID-19, despite the risk of late endoleak

Innate immune modulation by GM-CSF and IL-3 in health and disease

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inteleukin-3 (IL-3) have long been known as mediators of emergency myelopoiesis, but recent evidence has highlighted their critical role in modulating innate immune effector functions in mice and humans. This new wealth of knowledge has uncovered novel aspects of the pathogenesis of a range of disorders, including infectious, neoplastic, autoimmune, allergic and cardiovascular diseases. Consequently, GM-CSF and IL-3 are now being investigated as therapeutic targets for some of these disorders, and some phase I/II clinical trials are already showing promising results. There is also pre-clinical and clinical evidence that GM-CSF can be an effective immunostimulatory agent when being combined with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) in patients with metastatic melanoma as well as in novel cancer immunotherapy approaches. Finally, GM-CSF and to a lesser extent IL-3 play a critical role in experimental models of trained immunity by acting not only on bone marrow precursors but also directly on mature myeloid cells. Altogether, characterizing GM-CSF and IL-3 as central mediators of innate immune activation is poised to open new therapeutic avenues for several immune-mediated disorders and define their potential in the context of immunotherapies

Deterministic and stochastic chaos characterize laboratory earthquakes

We analyze frictional motion for a laboratory fault as it passes through the stability transition from stable sliding to unstable motion. We study frictional stick-slip events, which are the lab equivalent of earthquakes, via dynamical system tools in order to retrieve information on the underlying dynamics and to assess whether there are dynamical changes associated with the transition from stable to unstable motion. We find that the seismic cycle exhibits characteristics of a low-dimensional system with average dimension similar to that of natural slow earthquakes (<5). We also investigate local properties of the attractor and find maximum instantaneous dimension ≳10, indicating that some regions of the phase space require a high number of degrees of freedom (dofs). Our analysis does not preclude deterministic chaos, but the lab seismic cycle is best explained by a random attractor based on rate- and state-dependent friction whose dynamics is stochastically perturbed. We find that minimal variations of 0.05% of the shear and normal stresses applied to the experimental fault influence the large-scale dynamics and the recurrence time of labquakes. While complicated motion including period doubling is observed near the stability transition, even in the fully unstable regime we do not observe truly periodic behavior. Friction's nonlinear nature amplifies small scale perturbations, reducing the predictability of the otherwise periodic macroscopic dynamics. As applied to tectonic faults, our results imply that even small stress field fluctuations (≲150 kPa) can induce coefficient of variations in earthquake repeat time of a few percent. Moreover, these perturbations can drive an otherwise fast-slipping fault, close to the critical stability condition, into a mixed behavior involving slow and fast ruptures

Superantigenic Activation of Human Cardiac Mast Cells.

B cell superantigens, also called immunoglobulin superantigens, bind to the variable regions of either the heavy or light chain of immunoglobulins mirroring the lymphocyte-activating properties of classical T cell superantigens. Protein A of Staphylococcus aureus, protein L of Peptostreptococcus magnus, and gp120 of HIV are typical immunoglobulin superantigens. Mast cells are immune cells expressing the high-affinity receptor for IgE (FcεRI) and are strategically located in the human heart, where they play a role in several cardiometabolic diseases. Here, we investigated whether immunoglobulin superantigens induced the activation of human heart mast cells (HHMCs). Protein A induced the de novo synthesis of cysteinyl leukotriene C4 (LTC4) from HHMCs through the interaction with IgE VH3+ bound to FcεRI. Protein L stimulated the production of prostaglandin D2 (PGD2) from HHMCs through the interaction with κ light chains of IgE. HIV glycoprotein gp120 induced the release of preformed (histamine) and de novo synthesized mediators, such as cysteinyl leukotriene C4 (LTC4), angiogenic (VEGF-A), and lymphangiogenic (VEGF-C) factors by interacting with the VH3 region of IgE. Collectively, our data indicate that bacterial and viral immunoglobulin superantigens can interact with different regions of IgE bound to FcεRI to induce the release of proinflammatory, angiogenic, and lymphangiogenic factors from human cardiac mast cells.This work was supported in part by grants from Regione Campania CISI-Lab Project, CRèME Project, and TIMING Project

Heterogeneity of Human Mast Cells With Respect to MRGPRX2 Receptor Expression and Function.

Mast cells and their mediators play a role in the control of homeostasis and in the pathogenesis of several disorders. The concept of rodent mast cell heterogeneity, initially established in the mid-1960s has been extended in humans. Human mast cells isolated and purified from different anatomic sites can be activated via aggregation of cell surface high affinity IgE receptors (FcεRI) by antigens, superantigens, anti-IgE, and anti-FcεRI. MAS-related G protein-coupled receptor-X2 (MRGPRX2) is expressed at high level in human skin mast cells (MCs) (HSMCs), synovial MCs (HSyMCs), but not in lung MCs (HLMCs). MRGPX2 can be activated by neuropeptide substance P, several opioids, cationic drugs, and 48/80. Substance P (5 × 10-7 M - 5 × 10-6 M) induced histamine and tryptase release from HSMCs and to a lesser extent from HSyMCs, but not from HLMCs and human cardiac MCs (HHMCs). Morphine (10-5 M - 3 × 10-4 M) selectively induced histamine and tryptase release from HSMCs, but not from HLMCs and HHMCs. SP and morphine were incomplete secretagogues because they did not induce the de novo synthesis of arachidonic acid metabolites from human mast cells. In the same experiments anti-IgE (3 μg/ml) induced the release of histamine and tryptase and the de novo synthesis of prostaglandin D2 (PGD2) from HLMCs, HHMCs, HSyMCs, and HSMCs. By contrast, anti-IgE induced the production of leukotriene C4 (LTC4) from HLMCs, HHMCs, HSyMCs, but not from HSMCs. These results are compatible with the heterogeneous expression and function of MRGPRX2 receptor on primary human mast cells isolated from different anatomic sites.This work was supported partly by grants from the Regione Campania CISI-Lab Project, CRèME Project and TIMING Project

Renal handling of prednisolone/prednisone: effect of steroid dose and llβ-hydroxysteroid dehydrogenase

The purposes of this study were: (1) to determine under steady-state conditions whether the renal clearance of prednisolone is concentration dependent, and (2) to establish whether the urinary excretion of prednisolone and its biologically inactive 11-dehydro metabolite prednisone depend upon the activity of 11β-hydroxysteroid dehydrogenase (11β-OHSD). For that purpose 10 healthy volunteers were infused to steady state over a 13-h period either at a low (11 μg/h × kg) or a high (70 μg/h × kg) rate with prednisolone on two occasions, once without and once with administration of glycyrrhetinic acid, an inhibitor of 11β-OHSD. Prednisolone and prednisone were measured by high-pressure liquid chromatography. Mean renal clearance values of total or unbound prednisolone were several times higher during the high than the low infusion rate. The fractional renal clearance of unbound prednisolone during the high, but not during the low infusion rate exceeded 1. This indicates that in addition to unbound prednisolone, protein-bound prednisolone is excreted in urine at high plasma concentrations. Inhibition of 11β-OHSD increased the urinary ratios of prednisolone/prednisone in all subjects. Conclusions: (1) The renal clearance of prednisolone is concentration dependent; (2) there must be tubular secretion and/or glomerular filtration of prednisolone bound to plasma proteins; (3) the urinary excretion of prednisolone/prednisone is modulated by the activity of 11 β-OHS