Tuning cancer fate: the unremitting role of host immunity

Host immunity plays a central and complex role in dictating tumour progression. Solid tumours are commonly infiltrated by a large number of immune cells that dynamically interact with the surrounding microenvironment. At first, innate and adaptive immune cells successfully cooperate to eradicate microcolonies of transformed cells. Concomitantly, surviving tumour clones start to proliferate and harness immune responses by specifically hijacking anti-tumour effector mechanisms and fostering the accumulation of immunosuppressive immune cell subsets at the tumour site. This pliable interplay between immune and malignant cells is a relentless process that has been concisely organized in three different phases: elimination, equilibrium and escape. In this review, we aim to depict the distinct immune cell subsets and immune-mediated responses characterizing the tumour landscape throughout the three interconnected phases. Importantly, the identification of key immune players and molecules involved in the dynamic crosstalk between tumour and immune system has been crucial for the introduction of reliable prognostic factors and effective therapeutic protocols against cancers

Smoothing T cell roads to the tumor: Chemokine post-translational regulation

We described a novel tumor-associated immunosuppressive mechanism based on post-translational modifications of chemokines by reactive nitrogen species (RNS). To overcome tumor immunosuppressive hindrances, we designed and developed a new drug, AT38, that inhibits RNS generation at the tumor site. Combinatorial approaches with AT38 boost the effectiveness of cancer immunotherapy protocols

The Employment Crisis and Green Orientation in Agriculture: New Educational Models

Abstract This paper will address to the subject relating to the employment emergency and will analyze which are the conditions that can foster a green shared orientation among all stakeholders in the food system. So they can help to identify ways to solve this dramatic emergency. The study will be divided into three phases: 1. desk analysis on review of current training professional profiles green oriented; 2. evaluation of green employment, labor market and the current training system, with particular reference to the gap between the needs of businesses and provision of training in the sector; 3. thoughts on new green oriented professional profiles and the necessary training. The result will provide a first assessment of the state of art concerning this fundamental condition for the development of a green society

Abnormal temporal coupling of tactile perception and motor action in Parkinson's disease

Evidence shows altered somatosensory temporal discrimination threshold (STDT) in Parkinson's disease in comparison to normal subjects. In healthy subjects, movement execution modulates STDT values through mechanisms of sensory gating. We investigated whether STDT modulation during movement execution in patients with Parkinson's disease differs from that in healthy subjects. In 24 patients with Parkinson's disease and 20 healthy subjects, we tested STDT at baseline and during index finger abductions (at movement onset "0", 100, and 200 ms thereafter). We also recorded kinematic features of index finger abductions. Fifteen out of the 24 patients were also tested ON medication. In healthy subjects, STDT increased significantly at 0, 100, and 200 ms after movement onset, whereas in patients with Parkinson's disease in OFF therapy, it increased significantly at 0 and 100 ms but returned to baseline values at 200 ms. When patients were tested ON therapy, STDT during index finger abductions increased significantly, with a time course similar to that of healthy subjects. Differently from healthy subjects, in patients with Parkinson's disease, the mean velocity of the finger abductions decreased according to the time lapse between movement onset and the delivery of the paired electrical stimuli for testing somatosensory temporal discrimination. In conclusion, patients with Parkinson's disease show abnormalities in the temporal coupling between tactile information and motor outflow. Our study provides first evidence that altered temporal processing of sensory information play a role in the pathophysiology of motor symptoms in Parkinson's disease

Characterization by length heterogeneity (LH)-PCR of a hydrogen-producing community obtained in dark fermentation using coastal lake sediment as an inoculum

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Orchestration of lymphocyte chemotaxis by mitochondrial dynamics

Lymphocyte traffic is required to maintain homeostasis and perform appropriate immunological reactions. To migrate into inflamed tissues, lymphocytes must acquire spatial and functional asymmetries. Mitochondria are highly dynamic organelles that distribute in the cytoplasm to meet specific cellular needs, but whether this is essential to lymphocyte functions is unknown. We show that mitochondria specifically concentrate at the uropod during lymphocyte migration by a process involving rearrangements of their shape. Mitochondrial fission facilitates relocation of the organelles and promotes lymphocyte chemotaxis, whereas mitochondrial fusion inhibits both processes. Our data substantiate a new role for mitochondrial dynamics and suggest that mitochondria redistribution is required to regulate the motor of migrating cells

Oxidative stress by the mitochondrial monoamine oxidase B mediates calcium pyrophosphate crystal-induced arthritis

Objective: Calcium pyrophosphate (CPP) crystal deposition in the joints is associated with a heterogeneous set of debilitating syndromes characterized by inflammation and pain, for which no effective therapies are currently available. As we found that the mitochondrial enzyme monoamine oxidase B (MAO-B) plays a fundamental role in promoting inflammatory pathways, this study aims at assessing the efficacy of two clinical-grade inhibitors (iMAO-Bs) in preclinical models of this disease, to pave the way for a novel treatment. Methods: We tested our hypothesis in two murine models of CPP-induced arthritis, by measuring cytokine and chemokine levels, along with immune cell recruitment. iMAO-Bs (rasagiline and safinamide) were administered either before or after crystal injection. To elucidate the molecular mechanism, we challenged in vitro primed macrophages with CPP crystals and assessed the impact of iMAO-Bs in dampening proinflammatory cytokines and in preserving mitochondrial function. Results: Both in preventive and therapeutic in vivo protocols, iMAO-Bs blunted the release of proinflammatory cytokines (interleukin (IL)-6 and IL1-β) and chemokines (CXCL10, CXCL1, CCL2 and CCL5) (n>6 mice/group). Importantly, they also significantly reduced ankle swelling (50.3% vs 17.1% [P<0.001] and 23.1% [P=0.005] for rasagiline and safinamide, respectively). Mechanistically, iMAO-Bs dampened the burst of reactive oxygen species (ROS) and the mitochondrial dysfunction triggered by CPP crystals in isolated macrophages. Moreover, iMAO-Bs blunted cytokine secretion and NLRP3 inflammasome activation through inhibition of the NF-κB and STAT3 pathways. Conclusion: iMAO-Bs dampen inflammation in murine models of crystal-induced arthropathy, thereby uncovering MAO-B as a promising target to treat these diseases

Reactive Oxygen Species in Macrophages: Sources and Targets

Reactive oxygen species (ROS) are fundamental for macrophages to eliminate invasive microorganisms. However, as observed in nonphagocytic cells, ROS play essential roles in processes that are different from pathogen killing, as signal transduction, differentiation, and gene expression. The different outcomes of these events are likely to depend on the specific subcellular site of ROS formation, as well as the duration and extent of ROS production. While excessive accumulation of ROS has long been appreciated for its detrimental effects, there is now a deeper understanding of their roles as signaling molecules. This could explain the failure of the "all or none" pharmacologic approach with global antioxidants to treat several diseases. NADPH oxidase is the first source of ROS that has been identified in macrophages. However, growing evidence highlights mitochondria as a crucial site of ROS formation in these cells, mainly due to electron leakage of the respiratory chain or to enzymes, such as monoamine oxidases. Their role in redox signaling, together with their exact site of formation is only partially elucidated. Hence, it is essential to identify the specific intracellular sources of ROS and how they influence cellular processes in both physiological and pathological conditions to develop therapies targeting oxidative signaling networks. In this review, we will focus on the different sites of ROS formation in macrophages and how they impact on metabolic processes and inflammatory signaling, highlighting the role of mitochondrial as compared to non-mitochondrial ROS sources

Neurophysiological and clinical biomarkers of secondary progressive multiple sclerosis: A cross-sectional study

Timely diagnosis of secondary progressive multiple sclerosis (SPMS) represents a clinical challenge. The Frailty Index, a quantitative frailty measure, and the Neurophysiological Index, a combined measure of sensorimotor cortex inhibitory mechanism parameters, have recently emerged as promising tools to support SPMS diagnosis. The aim of this study was to explore the possible relationship between these two indices in MS. MS participants underwent a clinical evaluation, Frailty Index administration, and neurophysiological assessment. Frailty and Neurophysiological Index scores were found to be higher in SPMS and correlated with each other, thus suggesting that they may capture similar SPMS-related pathophysiological mechanisms