The weak ring of the chain : Immigrants facing the economic crisis in Italy

The article offers a synthetic overview of the main effects that the international economic crisis has had on immigrants in Italy. After a brief introductory explanation of the main characteristics of the Italian context of immigration, the authors concentrate on two main problems : the immigrants’ access to the labour market and to the housing system. The so-called “social vulnerability” of migrants was increased by the tensions related to the economic crisis. The growing problems that immigrants have been facing in the last three years are linked to the territorial distribution and to the mobility of the migrant communities on the national territory. The tendency to a progressive redistribution of the migratory destinations and to an increased mobility within and outside the Italian national borders are among the consequences of the socio-economic difficulties suffered by migrants. Finally, a few conclusive remarks suggest some policy recommendations.L’article offre une vue d’ensemble synthétique des effets principaux que la crise économique internationale a eus sur les immigrés en Italie. Après une brève explication des caractéristiques principales du contexte italien de l’immigration, les auteurs se concentrent sur deux problèmes principaux : l’accès des immigrés au marché du travail et au système de logement. La “vulnérabilité sociale” des migrants a été augmentée par les tensions liées à la crise économique. Les problèmes croissants que les immigrés ont rencontrés ces trois dernières années sont alors liés à la distribution territoriale et à la mobilité des communautés migratrices sur le territoire national. La tendance à une redistribution progressive des destinations migratrices et à une mobilité accrue dans et en dehors des frontières nationales italiennes sont parmi les conséquences des difficultés socio-économiques souffertes par les migrants. En conclusion, quelques remarques suggèrent une série de recommandations de politique

Enhancement of Heavy-Duty Engines Performance and Reliability Using Cylinder Pressure Information

Sustainability issues are becoming increasingly prominent in applications requiring the use of heavy-duty engines. Therefore, it is important to cut emissions and costs of such engines to re-duce the carbon footprint and keep the operating expenses under control. Even if for some applications a battery electric equipment is introduced, the diesel-equipped machinery is still popular, thanks to the longer operating range. In this field, the open pit mines are a good example. In fact, the Total Cost of Ownership (TCO) of the mining equipment is highly impacted by fuel consumption (engine efficiency) and reliability (service interval and en-gine life). The present work is focused on efficiency enhancements achievable through the ap-plication of a combustion control strategy based on the in-cylinder pressure information. The benefits are mainly due to two factors. First, the negative effects of injectors ageing can be com-pensated. Second, cylindrical online calibration of the control parameters enables the combus-tion system optimization. The article is divided into two parts. The first part describes the tool-chain that is designed for the real time application of the combustion control system, while the second part concerns the algorithm that would be implemented on the Engine Control Unit (ECU) to leverage the in-cylinder pressure information. The assessment of the potential benefits and feasibility of the combustion control algorithm is carried out in a Software in the Loop (SiL) environment, simulating both the developed control strategy and the engine behavior (Liebherr D98). Our goal is to validate the control algorithm through SiL simulations. The results of the validation process demonstrate the effectiveness of the control strategy: firstly, cylinder dispari-ty on IMEP (+/-2.5% in reference conditions) is virtually canceled. Secondly, MFB50 is individual-ly optimized, equalizing Pmax among the cylinders (+/-4% for the standard calibration), without exceeding the reliability threshold. In addition to this, BSFC is reduced by 1%, thanks to the ac-curate cylinder-by-cylinder calibration. Finally, ageing effects or fuel variations can be implicitly compensated, keeping optimal performance thorough engine life

Targeting the microenvironment in chronic lymphocytic leukemia offers novel therapeutic options

Chronic lymphocytic leukemia (CLL) cells display features consistent with a defect in apoptosis and exhibit prolonged survival in vivo. Survival of these malignant cells is influenced by interactions with non-leukemic cells located in permissive niches in lymphoid organs. Leukemic cells subvert the normal architecture of the lymphoid organs, recruiting stromal cells, dendritic cells and T lymphocytes, all reported as playing active roles in the survival and proliferation of CLL. The same survival-promoting environment also rescues/protects leukemic cells from cytotoxic therapies, giving way to disease relapse. This review summarizes and discusses current knowledge about the intricate network of soluble and cell-bound signals regulating the life and death of CLL cells in different districts. At the same time, it seeks to hone in on which discrete molecular elements are best suited as targets for treating this still incurable disease

Nitric oxide and P-glycoprotein modulate the phagocytosis of colon cancer cells

The anticancer drug doxorubicin induces the synthesis of nitric oxide, a small molecule that enhances the drug cytotoxicity and reduces the drug efflux through the membrane pump P-glycoprotein (Pgp). Doxorubicin also induces the translocation on the plasma membrane of the protein calreticulin (CRT), which allows tumour cells to be phagocytized by dendritic cells. We have shown that doxorubicin elicits nitric oxide synthesis and CRT exposure only in drug-sensitive cells, not in drug-resistant ones, which are indeed chemo-immunoresistant. In this work, we investigate the mechanisms by which nitric oxide induces the translocation of CRT and the molecular basis of this chemo-immunoresistance. In the drug-sensitive colon cancer HT29 cells doxorubicin increased nitric oxide synthesis, CRT exposure and cells phagocytosis. Nitric oxide promoted the translocation of CRT in a guanosine monophosphate (cGMP) and actin cytoskeleton-dependent way. CRT translocation did not occur in drug-resistant HT29-dx cells, where the doxorubicin-induced nitric oxide synthesis was absent. By increasing nitric oxide with stimuli other than doxorubicin, the CRT exposure was obtained also in HT29-dx cells. Although in sensitive cells the CRT translocation was followed by the phagocytosis, in drug-resistant cells the phagocytosis did not occur despite the CRT exposure. In HT29-dx cells CRT was bound to Pgp and only by silencing the latter the CRT-operated phagocytosis was restored, suggesting that Pgp impairs the functional activity of CRT and the tumour cells phagocytosis. Our work suggests that the levels of nitric oxide and Pgp critically modulate the recognition of the tumour cells by dendritic cells, and proposes a new potential therapeutic approach against chemo-immunoresistant tumours

RNAs competing for microRNAs mutually influence their fluctuations in a highly non-linear microRNA-dependent manner in single cells

We used an experimental design based on two bidirectional plasmids and flow cytometry measurements of cotransfected mammalian cells. We validated a stochastic gene interaction model that describes how mRNAs can influence each other’s fluctuations in a miRNA-dependent manner in single cells. We show that miRNA–target correlations eventually lead to either bimodal cell population distributions with high and low target expression states, or correlated fluctuations across targets when the pool of unbound targets and miRNAs are in near-equimolar concentration. We found that there is an optimal range of conditions for the onset of cross-regulation, which is compatible with 10–1000 copies of targets per cell

Correlation between NK function and response to trastuzumab in metastatic breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Trastuzumab is a monoclonal antibody selectively directed against Her2 and approved for the treatment of Her2 overexpressing breast cancer patients. Its proposed mechanisms of action include mediation of antibody-dependent cellular cytotoxicity (ADCC) by triggering FcγRIII on natural killer (NK) cells. This study addresses the correlation between overall NK function and trastuzumab's clinical activity.</p> <p>Subjects and methods</p> <p>Clinical and immunological responses were assessed in 26 patients receiving trastuzumab monotherapy as maintenance management after chemotherapy (8 mg/kg load and then standard doses of 6 mg/kg every 3 weeks). Cytotoxic activity against the MHC class I-negative standard NK target K562 cell line and HER2-specific ADCC against a trastuzumab-coated Her2-positive SKBR3 cell line were assessed in peripheral blood mononuclear cells (PBMC) harvested after the first standard dose. After six months, seventeen patients were scored as responders and nine as non-responders according to the RECIST criteria, while Progression-Free Survival (PFS) was calculated during a 12 months follow-up.</p> <p>Results</p> <p>The responders had significantly higher levels of both NK and ADCC activities (p < 0.05) that were not different from those of eleven normal controls. The NK activity of the non-responders was significantly (p < 0.05) lower than that of the normal controls. At twelve months, there was a marked correlation between PFS and NK activity only. PFS was significantly longer in patients with high levels of NK activity, whereas its pattern was unrelated to high or low ADCC activity.</p> <p>Conclusion</p> <p>One of the mechanisms of action of trastuzumab is NK cell-mediated ADCC lysis of the Her2-positve target cell. We show here that its potency is correlated with the short-term response to treatment, whereas longer protection against tumor expansion seems to be mediated by pure NK activity.</p

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

The chronic lymphocytic leukemia (CLL) niche is a closed environment where leukemic cells derive growth and survival signals through their interaction with macrophages and T lymphocytes. Here, we show that the CLL lymph node niche is characterized by overexpression and activation of HIF-1a, which increases adenosine generation and signaling, affecting tumor and host cellular responses. Hypoxia in CLL lymphocytes modifies central metabolic pathways, protects against drug-driven apoptosis, and induces interleukin 10 (IL-10) production. In myeloid cells, it forces monocyte differentiation to macrophages expressing IRF4, IDO, CD163, and CD206, hallmarks of the M2 phenotype, which promotes tumor progression. It also induces IL-6 production and enhances nurturing properties. Low oxygen levels decrease T-cell proliferation, promote glycolysis, and cause the appearance of a population of PD-11 and IL-10–secreting T cells. Blockade of the A2A adenosine receptor counteracts these effects on all cell populations, making leukemic cells more susceptible to pharmacological agents while restoring immune competence and T-cell proliferation. Together, these results indicate that adenosine signaling through the A2A receptor mediates part of the effects of hypoxia. They also suggest that therapeutic strategies to inhibit the adenosinergic axis may be useful adjuncts to chemotherapy or tyrosine kinase inhibitors in the treatment of CLL patients

SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans.

OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i), or gliflozins, are anti-diabetic drugs that lower glycemia by promoting glucosuria, but they also stimulate endogenous glucose and ketone body production. The likely causes of these metabolic responses are increased blood glucagon levels, and decreased blood insulin levels, but the mechanisms involved are hotly debated. This study verified whether or not SGLT2i affect glucagon and insulin secretion by a direct action on islet cells in three species, using multiple approaches. METHODS: We tested the in vivo effects of two selective SGLT2i (dapagliflozin, empagliflozin) and a SGLT1/2i (sotagliflozin) on various biological parameters (glucosuria, glycemia, glucagonemia, insulinemia) in mice. mRNA expression of SGLT2 and other glucose transporters was assessed in rat, mouse, and human FACS-purified α- and β-cells, and by analysis of two human islet cell transcriptomic datasets. Immunodetection of SGLT2 in pancreatic tissues was performed with a validated antibody. The effects of dapagliflozin, empagliflozin, and sotagliflozin on glucagon and insulin secretion were assessed using isolated rat, mouse and human islets and the in situ perfused mouse pancreas. Finally, we tested the long-term effect of SGLT2i on glucagon gene expression. RESULTS: SGLT2 inhibition in mice increased the plasma glucagon/insulin ratio in the fasted state, an effect correlated with a decline in glycemia. Gene expression analyses and immunodetections showed no SGLT2 mRNA or protein expression in rodent and human islet cells, but moderate SGLT1 mRNA expression in human α-cells. However, functional experiments on rat, mouse, and human (29 donors) islets and the in situ perfused mouse pancreas did not identify any direct effect of dapagliflozin, empagliflozin or sotagliflozin on glucagon and insulin secretion. SGLT2i did not affect glucagon gene expression in rat and human islets. CONCLUSIONS: The data indicate that the SGLT2i-induced increase of the plasma glucagon/insulin ratio in vivo does not result from a direct action of the gliflozins on islet cells