Emerging roles of purinergic signaling in anti-cancer therapy resistance

Cancer is a complex disease with a rapid growing incidence and often characterized by a poor prognosis. Although impressive advances have been made in cancer treatments, resistance to therapy remains a critical obstacle for the improvement of patients outcome. Current treatment approaches as chemo-, radio-, and immuno-therapy deeply affect the tumor microenvironment (TME), inducing an extensive selective pressure on cancer cells through the activation of the immune system, the induction of cell death and the release of inflammatory and damage-associated molecular patterns (DAMPS), including nucleosides (adenosine) and nucleotides (ATP and ADP). To survive in this hostile environment, resistant cells engage a variety of mitigation pathways related to metabolism, DNA repair, stemness, inflammation and resistance to apoptosis. In this context, purinergic signaling exerts a pivotal role being involved in mitochondrial function, stemness, inflammation and cancer development. The activity of ATP and adenosine released in the TME depend upon the repertoire of purinergic P2 and adenosine receptors engaged, as well as, by the expression of ectonucleotidases (CD39 and CD73) on tumor, immune and stromal cells. Besides its well established role in the pathogenesis of several tumors and in host–tumor interaction, purinergic signaling has been recently shown to be profoundly involved in the development of therapy resistance. In this review we summarize the current advances on the role of purinergic signaling in response and resistance to anti-cancer therapies, also describing the translational applications of combining conventional anticancer interventions with therapies targeting purinergic signaling

The generation of images of surface structures by laser-accelerated protons

Ion acceleration by lasers is one of the most important innovations in laser-plasma research in recent years. A mechanism that has gained great attention due to the remarkable properties of the accelerated beam is laser acceleration of protons from the rear surface of solid targets. A striking prediction is that these protons are capable of generating images of micro-structures present on this surface. These images might be useful to measure properties of the accelerated beam. In this article, we address the physics of the generation of images of surface structures imprinted into the target back surface with laser-accelerated protons

Coupling between reconnection and Kelvin-Helmholtz instabilities in collisionless plasmas

In a collisionless plasma, when reconnection instability takes place, strong shear flows may develop. Under appropriate conditions these shear flows become unstable to the Kelvin-Helmholtz instability. Here, we investigate the coupling between these instabilities in the framework of a four-field model. Firstly, we recover the known results in the low β limit, β being the ratio between the plasma and the magnetic pressure. We concentrate our attention on the dynamical evolution of the current density and vorticity sheets which evolve coupled together according to a laminar or a turbulent regime. A three-dimensional extension in this limit is also discussed. Secondly, we consider finite values of the β parameter, allowing for compression of the magnetic and velocity fields along the ignorable direction. We find that the current density and vorticity sheets now evolve separately. The Kelvin-Helmholtz instability involves only the vorticity field, which ends up in a turbulent regime, while the current density maintains a laminar structure

Coupling between reconnection and Kelvin-Helmholtz instabilities in collisionless plasmas

Abstract. In a collisionless plasma, when reconnection instability takes place, strong shear flows may develop. Under appropriate conditions these shear flows become unstable to the Kelvin-Helmholtz instability. Here, we investigate the coupling between these instabilities in the framework of a four-field model. Firstly, we recover the known results in the low β limit, β being the ratio between the plasma and the magnetic pressure. We concentrate our attention on the dynamical evolution of the current density and vorticity sheets which evolve coupled together according to a laminar or a turbulent regime. A three-dimensional extension in this limit is also discussed. Secondly, we consider finite values of the β parameter, allowing for compression of the magnetic and velocity fields along the ignorable direction. We find that the current density and vorticity sheets now evolve separately. The Kelvin-Helmholtz instability involves only the vorticity field, which ends up in a turbulent regime, while the current density maintains a laminar structure

Unimpaired Neuropsychological Performance and Enhanced Memory Recall in Patients with Sbma: A Large Sample Comparative Study.

Peculiar cognitive profile of patients with SBMA has been described by fragmented literature. Our retrospective study reports the neuropsychological evaluations of a large cohort of patients in order to contribute towards the understanding of this field. We consider 64 neuropsychological evaluations assessing mnesic, linguistic and executive functions collected from 2013 to 2015 in patients attending at Motor Neuron Disease Centre of University of Padova. The battery consisted in: Digit Span forwards and backwards, Prose Memory test, Phonemic Verbal fluency and Trail making tests. ANCOVA statistics were employed to compare tests scores results with those obtained from a sample of healthy control subjects. Multiple linear regressions were used to study the effect on cognitive performance of CAG-repeat expansion, the degree of androgen insensitivity and their interaction to cognitive performance. Statistical analyses did not reveal altered scores in any neuropsychological tests among those adopted. Interestingly, patients performed significantly better in the Prose Memory test's score. No relevant associations were found with genetic, hormonal or clinical patients' profile. Results inconsistent with previous studies have been interpreted according to the phenomenon of somatic mosaicism. We suggest a testosterone-related and the mood state-dependant perspectives as two possible interpretations of the enhanced performances in the Prose Memory test. Further studies employing more datailed tests batteries are encouraged

Ethical difficulties in clinical practice : experiences of European doctors

Background: Ethics support services are growing in Europe to help doctors in dealing with ethical difficulties. Currently, insufficient attention has been focused on the experiences of doctors who have faced ethical difficulties in these countries to provide an evidence base for the development of these services. Methods: A survey instrument was adapted to explore the types of ethical dilemma faced by European doctors, how they ranked the difficulty of these dilemmas, their satisfaction with the resolution of a recent ethically difficult case and the types of help they would consider useful. The questionnaire was translated and given to general internists in Norway, Switzerland, Italy and the UK. Results: Survey respondents (n = 656, response rate 43%) ranged in age from 28 to 82 years, and averaged 25 years in practice. Only a minority (17.6%) reported having access to ethics consultation in individual cases. The ethical difficulties most often reported as being encountered were uncertain or impaired decisionmaking capacity (94.8%), disagreement among caregivers (81.2%) and limitation of treatment at the end of life (79.3%). The frequency of most ethical difficulties varied among countries, as did the type of issue considered most difficult. The types of help most often identified as potentially useful were professional reassurance about the decision being correct (47.5%), someone capable of providing specific advice (41.1%), help in weighing outcomes (36%) and clarification of the issues (35.9%). Few of the types of help expected to be useful varied among countries. Conclusion: Cultural differences may indeed influence how doctors perceive ethical difficulties. The type of help needed, however, did not vary markedly. The general structure of ethics support services would not have to be radically altered to suit cultural variations among the surveyed countries

Enhancing proton acceleration by using composite targets

Efficient laser ion acceleration requires high laser intensities, which can only be obtained by tightly focusing laser radiation. In the radiation pressure acceleration regime, where the tightly focused laser driver leads to the appearance of the fundamental limit for the maximum attainable ion energy, this limit corresponds to the laser pulse group velocity as well as to another limit connected with the transverse expansion of the accelerated foil and consequent onset of the foil transparency. These limits can be relaxed by using composite targets, consisting of a thin foil followed by a near critical density slab. Such targets provide guiding of a laser pulse inside a self-generated channel and background electrons, being snowplowed by the pulse, compensate for the transverse expansion. The use of composite targets results in a significant increase in maximum ion energy, compared to a single foil target case.Comment: 16 pages, 9 figure

Radiation Pressure Acceleration: the factors limiting maximum attainable ion energy

Radiation pressure acceleration (RPA) is a highly efficient mechanism of laser-driven ion acceleration, with with near complete transfer of the laser energy to the ions in the relativistic regime. However, there is a fundamental limit on the maximum attainable ion energy, which is determined by the group velocity of the laser. The tightly focused laser pulses have group velocities smaller than the vacuum light speed, and, since they offer the high intensity needed for the RPA regime, it is plausible that group velocity effects would manifest themselves in the experiments involving tightly focused pulses and thin foils. However, in this case, finite spot size effects are important, and another limiting factor, the transverse expansion of the target, may dominate over the group velocity effect. As the laser pulse diffracts after passing the focus, the target expands accordingly due to the transverse intensity profile of the laser. Due to this expansion, the areal density of the target decreases, making it transparent for radiation and effectively terminating the acceleration. The off-normal incidence of the laser on the target, due either to the experimental setup, or to the deformation of the target, will also lead to establishing a limit on maximum ion energy.Comment: 17 pages, 6 figure