884 research outputs found
Immunity, inflammation and cancer: a leading role for adenosine
No full textCancer is a complex disease that is dictated by both cancer cell-intrinsic and cell-extrinsic processes. Adenosine is an ancient extracellular signalling molecule that can regulate almost all aspects of tissue function. As such, several studies have recently highlighted a crucial role for adenosine signalling in regulating the various aspects of cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses the role of adenosine and its receptors in regulating the complex interplay among immune, inflammatory, endothelial and cancer cells during the course of neoplastic disease
Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations
No full textAdenosine is a key extracellular signalling molecule that regulates several aspects of tissue function by activating four G-protein-coupled receptors, A1, A2A, A2B and A1 adenosine receptors. Accumulating evidence highlights a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Although adenosine signalling is known to affect insulin secretion, new data indicate that adenosine signalling also contributes to the regulation of β-cell homeostasis and activity by controlling the proliferation and regeneration of these cells as well as the survival of β cells in inflammatory microenvironments. Furthermore, adenosine is emerging as a major regulator of insulin responsiveness by controlling insulin signalling in adipose tissue, muscle and liver; adenosine also indirectly mediates effects on inflammatory and/or immune cells in these tissues. This Review critically discusses the role of the adenosine-adenosine receptor system in regulating both the onset and progression of T1DM and T2DM, and the potential of pharmacological manipulation of the adenosinergic system as an approach to manage T1DM, T2DM and their associated complications
Adenosine signaling and the immune system: When a lot could be too much
No full textAdenosine is increasingly recognized as a key mediator of the immune response. Signals delivered by extracellular adenosine are detected and transduced by G-protein-coupled cell-surface receptors, classified into four subtypes: A1, A2A, A2Band A3. These receptors, expressed virtually on all immune cells, modulate all aspects of immune/inflammatory responses. These immunoregulatory effects, which are mostly anti-inflammatory, contribute to the general tissue protective effects of adenosine and its receptors. In some instances, however, the effect of adenosine on the immune system is deleterious, as prolonged adenosine signaling can hinder anti-tumor and antibacterial immunity, thereby promoting cancer development and progression and sepsis, respectively
Adenosine signaling as target in cardiovascular pharmacology
No full textIncreasing evidence demonstrated the relevance of adenosine system in the onset and development of cardiovascular dis-eases, such as hypertension, myocardial infarct, ischemia, hypertension, heart failure, and atherosclerosis. In this regard, intense research efforts are being focused on the character-ization of the pathophysiological significance of adenosine, acting at its membrane receptors named A1, A2A, A2B, and A3 receptors, in cardiovascular diseases. The present review article provides an integrated and comprehensive overview about current clinical and pre-clinical evidence about the role of adenosine in the pathophysiology of cardiovascular diseases. Particular attention has been focused on current scientific ev-idence about the pharmacological ligands acting on adenosine pathway as useful tools to manage cardiovascular diseases
CD39 and CD73 in immunity and inflammation
No full textThe enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to immune cells through the conversion of ADP/ATP to AMP and AMP to adenosine, respectively. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39/CD73 pathway changes dynamically with the pathophysiological context in which it is embedded. It is becoming increasingly appreciated that altering this catabolic machinery can change the course or dictate the outcome of several pathophysiological events, such as AIDS, autoimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, and cancer, suggesting these ectoenzymes are novel therapeutic targets for managing a variety of disorders
Rethinking Communication in the Immune System: The Quorum Sensing Concept
No full textQuorum sensing was first described as the communication process bacteria employ to coordinate changes in gene expression and therefore, their collective behavior in response to population density. Emerging new evidence suggests that quorum sensing can also contribute to the regulation of immune cell responses. Quorum sensing might be achieved by the ability of immune cells to perceive the density of their own populations or those of other cells in their environment; responses to alterations in cell density might then be coordinated via changes in gene expression and protein signaling. Quorum sensing mechanisms can regulate T and B cell as well as macrophage function. We posit that perturbations in quorum sensing may undermine the balance between diverse immune cell populations and predispose the host to immune abnormalities
Anti-CD73 in cancer immunotherapy: awakening new opportunities
No full textIn recent years, cancer immunotherapy made significant advances due to a better understanding of the principles underlying tumor biology and immunology. In this context, CD73 is a key molecule, since via degradation of adenosine monophosphate into adenosine, endorses the generation of an immunosuppressed and pro-angiogenic niche within the tumor microenvironment that promotes the onset and progression of cancer. Targeting CD73 results in favorable antitumor effects in pre-clinical models and combined treatments of CD73 blockade with other immune-modulating agents (i.e. anti-CTLA-4 mAb or anti-PD1 mAb) is particularly attractive. Although there is still a long way to go, anti-CD73 therapy, through the development of CD73 monoclonal antibodies, can potentially constitute a new biologic therapy for cancer patients. In this review, we discuss the link between CD73 and the onset, development and spread of tumors, highlighting the potential value of this molecule as a target and as a novel biomarker in the context of personalized cancer therapy
Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing
No full textExtracellular ATP binds to and signals through P2X7 receptors (P2X7Rs) to modulate immune function in both inflammasome-dependent and -independent manners. In this study, P2X7-/- mice, the pharmacological agonists ATP-magnesium salt (Mg-ATP; 100 mg/kg, EC50 ≈ 1.32 mM) and benzoylbenzoyl-ATP (Bz-ATP; 10 mg/kg, EC50 ≈ 285 μM), and antagonist oxidized ATP (oxi-ATP; 40 mg/kg, IC50 ≈ 100 μM) were used to show that P2X7R activation is crucial for the control of mortality, bacterial dissemination, and inflammation in cecal ligation and puncture-induced polymicrobial sepsis in mice. Our results with P2X7-/- bone marrow chimeric mice, adoptive transfer of peritoneal macrophages, and myeloid-specific P2X7-/- mice indicate that P2X7R signaling on macrophages is essential for the protective effect of P2X7Rs. P2X7R signaling protects through enhancing bacterial killing by macrophages, which is independent of the inflammasome. By using the connexin (Cx) channel inhibitor Gap27 (0.1 mg/kg, IC50 ≈ 0.25 μM) and pannexin channel inhibitor probenecid (10 mg/kg, IC50 ≈ 11.7 μM), we showed that ATP release through Cx is important for inhibiting inflammation and bacterial burden. In summary, targeting P2X7Rs provides a new opportunity for harnessing an endogenous protective immune mechanism in the treatment of sepsis.-Csóka, B., Németh, Z. H., Töro, G., Idzko, M., Zech, A., Koscsó, B., Spolarics, Z., Antonioli, L., Cseri, K., Erdélyi, K., Pacher, P., Haskó, G. Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing
Estimation of melt pool size by complementary use of external illumination and process emission in coaxial monitoring of selective laser melting
No full textCoaxial imaging of melt pool dynamics provides several advantages over other monitoring methods in selective laser melting (SLM). The ability to track the processing zone ensures the possibility to observe defect formation dynamics mainly related to melting and solidication. Commonly, the melt pool dynamics are observed by means of process emission. In process emission images, geometrical information of the melt pool is not directly available and their extraction would require the use of a calibrated sensor in order to measure the temperature levels; as a consequence, commonly an arbitrary threshold is applied to the image. The use of external illumination for monitoring purposes allows for suppressing the process emission and observing the melt pool geometry by means of the reected light. On the other hand, the obtained images show lower contrast and can be difcult to process by means of image processing algorithms. Accordingly, this work proposes the complementary use of external illumination to calibrate the melt pool geometry. Afterward, the process emission and melt pool dynamics in SLM are characterized. For the purpose, an open SLM platform with an in-house designed coaxial monitoring module is used. Images with external illumination were used to estimate the melt pool size for AISI 316L stainless steel. The information was used to set a threshold value for determining the melt pool size observed at the near-infrared emission band. The proposed strategy proved promising for real time monitoring and control applications and can represent a feasible solution for industrial systems
New development on digital architecture for efficient pixel readout ASIC at extreme hit rate for hep detectors at HL-LHC
No full textA novel region-based pixel digital architecture for latency buffering and trigger matching able to withstand extended trigger latencies and unprecedented data rates at the High-Luminosity LHC upgrade is presented. The architecture features above 99.5% efficiency at nominal 3 GHz/cm 2 pixel hit rate and 1 MHz trigger rate with 12.5 μs trigger latency foreseen at HL-LHC. The overall inefficiency is dominated by dead-time in analogue front-end channels. The digital architecture is organized in pixel regions composed of 4×4 pixels. Charge information is retrieved from each pixel by means of Time-over-Threshold (ToT) using 5-bit counters. A common digital logic shared among pixels stores hits information for the whole trigger latency, handles the local configuration, performs trigger matching and sends zero-suppressed hit data to the chip periphery upon a trigger request. Data compression based on priority queues has been introduced in order to save area and power in the pixel region. The logic has been implemented in a commercial 65 nm CMOS pixel ASIC demonstrator prototyped as part of the Italian INFN CHIPIX65 project. Design specifications, implementation details and simulation results are discussed
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