Il coraggio degli infermieri ai tempi del COVID-19

La diffusione del SARS-COV-2 è stata annunciata a partire dal 9 gennaio 2020, quando l'Organizzazione Mondiale della Sanità (OMS) ha dichiarato che le autorità sanitarie cinesi avevano individuato un nuovo ceppo di coronavirus mai prima identificato nel genere umano. Il virus è stato chiamato dapprima 2019-nCoV, per poi essere ufficialmente e definitivamente classificato con il nome di SARS-CoV-2. La sua diffusione è stata associata a un focolaio di polmoniti segnalato il 31 dicembre 2019 in Cina, nella sua parte centrale, nella città di Wuhan. La malattia respiratoria causata dal nuovo coronavirus ha preso il nome di COVID-19 con dichiarazione dell'OMS del seguente 11 febbraio. I primi due casi presenti in Italia sono stati confermati dall'Istituto Superiore di Sanità (ISS) in data 30 gennaio, successivamente il 21 febbraio è stato individuato un nuovo caso, identificato come il primo caso autoctono su territorio nazionale1. In seguito alla velocità e alla dimensione del contagio da parte del nuovo virus, l’OMS, in data 11 marzo 2020 ha dichiarato che l’infezione internazionale poteva essere considerata una pandemia. Dall’inizio della diffusione del virus, la pandemia ha creato danni enormi in tutti i Paesi del globo, con milioni di persone che hanno perso la vita. Gli infermieri e gli operatori dei sistemi sanitari nazionali di tutti i Paesi colpiti hanno visto stravolgere le proprie vite e i propri setting lavorativi in maniera repentina per far fronte con coraggio a questa pandemia, spesso non senza conseguenze. Infatti, basti considerare che in Italia il 72,2% dei contagi sul lavoro avvengono nel settore sanitario e di questi l’83% è rappresentato dagli infermieri, e in totale si contano una percentuale che ha superato, in alcune fasi della pandemia, anche il 15% di tutti i casi di COVID19 su territorio nazionale.La diffusione del SARS-COV-2 è stata annunciata a partire dal 9 gennaio 2020, quando l'Organizzazione Mondiale della Sanità (OMS) ha dichiarato che le autorità sanitarie cinesi avevano individuato un nuovo ceppo di coronavirus mai prima identificato nel genere umano. Il virus è stato chiamato dapprima 2019-nCoV, per poi essere ufficialmente e definitivamente classificato con il nome di SARS-CoV-2. La sua diffusione è stata associata a un focolaio di polmoniti segnalato il 31 dicembre 2019 in Cina, nella sua parte centrale, nella città di Wuhan. La malattia respiratoria causata dal nuovo coronavirus ha preso il nome di COVID-19 con dichiarazione dell'OMS del seguente 11 febbraio. I primi due casi presenti in Italia sono stati confermati dall'Istituto Superiore di Sanità (ISS) in data 30 gennaio, successivamente il 21 febbraio è stato individuato un nuovo caso, identificato come il primo caso autoctono su territorio nazionale1. In seguito alla velocità e alla dimensione del contagio da parte del nuovo virus, l’OMS, in data 11 marzo 2020 ha dichiarato che l’infezione internazionale poteva essere considerata una pandemia. Dall’inizio della diffusione del virus, la pandemia ha creato danni enormi in tutti i Paesi del globo, con milioni di persone che hanno perso la vita. Gli infermieri e gli operatori dei sistemi sanitari nazionali di tutti i Paesi colpiti hanno visto stravolgere le proprie vite e i propri setting lavorativi in maniera repentina per far fronte con coraggio a questa pandemia, spesso non senza conseguenze. Infatti, basti considerare che in Italia il 72,2% dei contagi sul lavoro avvengono nel settore sanitario e di questi l’83% è rappresentato dagli infermieri, e in totale si contano una percentuale che ha superato, in alcune fasi della pandemia, anche il 15% di tutti i casi di COVID19 su territorio nazionale

CCR2 acts as scavenger for CCL2 during monocyte chemotaxis

Background: Leukocyte migration is essential for effective host defense against invading pathogens and during immune homeostasis. A hallmark of the regulation of this process is the presentation of chemokines in gradients stimulating leukocyte chemotaxis via cognate chemokine receptors. For efficient migration, receptor responsiveness must be maintained whilst the cells crawl on cell surfaces or on matrices along the attracting gradient towards increasing concentrations of agonist. On the other hand agonist-induced desensitization and internalization is a general paradigm for chemokine receptors which is inconsistent with the prolonged migratory capacity. Methodology/Principal Findings: Chemotaxis of monocytes was monitored in response to fluorescent CCL2-mCherry by time-lapse video microscopy. Uptake of the fluorescent agonist was used as indirect measure to follow the endogenous receptor CCR2 expressed on primary human monocytes. During chemotaxis CCL2-mCherry becomes endocytosed as cargo of CCR2, however, the internalization of CCR2 is not accompanied by reduced responsiveness of the cells due to desensitization. Conclusions/Significance: During chemotaxis CCR2 expressed on monocytes internalizes with the bound chemoattractant, but cycles rapidly back to the plasma membrane to maintain high responsiveness. Moreover, following relocation of the source of attractant, monocytes can rapidly reverse their polarization axis organizing a new leading edge along the newly formed gradient, suggesting a uniform distribution of highly receptive CCR2 on the plasma membrane. The present observations further indicate that during chemotaxis CCR2 acts as scavenger consuming the chemokine forming the attracting cue

CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice

Current combined surgical and neo-adjuvant chemotherapy of primary metastatic osteosarcoma (OS) is ineffective, reflected by a 5-year survival rate of affected patients of less than 20%. Studies in experimental OS metastasis models pointed to the CXCR4/CXCL12 homing axis as a novel target for OS metastasis-suppressive treatment. The present study investigated for the first time the CXCR4-blocking principle in a spontaneously metastasizing human 143B OS cell line-derived orthotopic xenograft mouse model. The highly metastatic 143B cells, unlike the parental non-metastatic HOS cells, express functional CXCR4 receptors at the cell surface, as revealed in this study by RT/PCR of gene transcripts, by FACS analysis with the monoclonal anti CXCR4 antibody 12G5 (mAb 12G5) and by CXCL12 time- and dose-dependent stimulation of AKT and ERK phosphorylation. A significantly (p<0.05) higher CXCL12 dose-dependent chemotactic response of 143B compared to HOS cells in a Boyden chamber trans-well migration assay suggested a crucial role of the CXCL12/CXCR4 homing axis in 143B cell lung metastasis. Repetitive treatment of mice with 143B cell-derived intratibial tumors given intravenous bolus injections of mAb12G5 indeed inhibited significantly (p<0.01) the number of X-gal-stainable lung micrometastases of lacZ-transduced 143B cells. Antibody treatment had also a mild inhibitory effect on primary tumor growth associated with remarkably less osteolysis, but it did not affect the number of developing lung macrometastases. In conclusion, these results demonstrate considerable potential of high-affinity CXCR4-blocking agents for OS tumor cell homing suppressive treatment in metastasizing OS complementary to current (neo)-adjuvant chemotherapy

CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis

Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6- progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target. © 2014 Elsevier Inc

HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4

After tissue damage, inflammatory cells infiltrate the tissue and release proinflammatory cytokines. HMGB1 (high mobility group box 1), a nuclear protein released by necrotic and severely stressed cells, promotes cytokine release via its interaction with the TLR4 (Toll-like receptor 4) receptor and cell migration via an unknown mechanism. We show that HMGB1- induced recruitment of inflammatory cells depends on CXCL12. HMGB1 and CXCL12 form a heterocomplex, which we characterized by nuclear magnetic resonance and surface plasmon resonance, that acts exclusively through CXCR4 and not through other HMGB1 receptors. Fluorescence resonance energy transfer data show that the HMGB1–CXCL12 heterocomplex promotes different conformational rearrangements of CXCR4 from that of CXCL12 alone. Mononuclear cell recruitment in vivo into air pouches and injured muscles depends on the heterocomplex and is inhibited by AMD3100 and glycyrrhizin. Thus, inflammatory cell recruitment and activation both depend on HMGB1 via different mechanisms

CCR2 Acts as Scavenger for CCL2 during Monocyte Chemotaxis

<div><h3>Background</h3><p>Leukocyte migration is essential for effective host defense against invading pathogens and during immune homeostasis. A hallmark of the regulation of this process is the presentation of chemokines in gradients stimulating leukocyte chemotaxis via cognate chemokine receptors. For efficient migration, receptor responsiveness must be maintained whilst the cells crawl on cell surfaces or on matrices along the attracting gradient towards increasing concentrations of agonist. On the other hand agonist-induced desensitization and internalization is a general paradigm for chemokine receptors which is inconsistent with the prolonged migratory capacity.</p> <h3>Methodology/Principal Findings</h3><p>Chemotaxis of monocytes was monitored in response to fluorescent CCL2-mCherry by time-lapse video microscopy. Uptake of the fluorescent agonist was used as indirect measure to follow the endogenous receptor CCR2 expressed on primary human monocytes. During chemotaxis CCL2-mCherry becomes endocytosed as cargo of CCR2, however, the internalization of CCR2 is not accompanied by reduced responsiveness of the cells due to desensitization.</p> <h3>Conclusions/Significance</h3><p>During chemotaxis CCR2 expressed on monocytes internalizes with the bound chemoattractant, but cycles rapidly back to the plasma membrane to maintain high responsiveness. Moreover, following relocation of the source of attractant, monocytes can rapidly reverse their polarization axis organizing a new leading edge along the newly formed gradient, suggesting a uniform distribution of highly receptive CCR2 on the plasma membrane. The present observations further indicate that during chemotaxis CCR2 acts as scavenger consuming the chemokine forming the attracting cue.</p> </div