The Steiner problem for infinitely many points

Let AA be a given compact subset of the euclidean space. We consider the problem of finding a compact connected set SS of minimal 11-dimensional Hausdorff measure, among all compact connected sets containing AA. We prove that when AA is a finite set any minimizer is a finite tree with straight edges, thus recovery the classical Steiner Problem. Analogously, in the case when AA is countable, we prove that every minimizer is a (possibly) countable union of straight segments

The S0_0(0) structure in highly compressed hydrogen and the orientational transition

A calculation of the rotational S$_0$(0) frequencies in high pressure solid para-hydrogen is performed. Convergence of the perturbative series at high density is demonstrated by the calculation of second and third order terms. The results of the theory are compared with the available experimental data to derive the density behaviour of structural parameters. In particular, a strong increase of the value of the lattice constant ratio $c/a$ and of the internuclear distance is determined. Also a decrease of the anisotropic intermolecular potential is observed which is attributed to charge transfer effects. The structural parameters determined at the phase transition may be used to calculate quantum properties of the rotationally ordered phase.Comment: accepted Europhysics Letter

Cerebral venous thrombosis: a practical guide

All neurologists need to be able to recognise and treat cerebral venous thrombosis (CVT). It is difficult to diagnose, partly due to its relative rarity, its multiple and various clinical manifestations (different from ‘conventional’ stroke, and often mimicking other acute neurological conditions), and because it is often challenging to obtain and interpret optimal and timely brain imaging. Although CVT can result in death or permanent disability, it generally has a favourable prognosis if diagnosed and treated early. Neurologists involved in stroke care therefore also need to be aware of the treatments for CVT (with varying degrees of supporting evidence): the mainstay is prompt anticoagulation but patients who deteriorate despite treatment can be considered for endovascular procedures (endovascular thrombolysis or thrombectomy) or neurosurgery (decompressive craniotomy). This review summarises current knowledge on the risk factors, diagnosis, treatment and prognosis of CVT in adults, and highlights some areas for future research

Pressure-tuning of the electron-phonon coupling: the insulator to metal transition in manganites

A comprehensive understanding of the physical origin of the unique magnetic and transport properties of A_(1-x)A'^xMnO_3 manganites (A = trivalent rare-earth and A' = divalent alkali-earth metal) is still far from being achieved. The complexity of these systems arises from the interplay among several competing interactions of comparable strength. Recently the electron-phonon coupling, triggered by a Jahn-Teller distortion of the MnO_6 octahedra, has been recognised to play an essential role in the insulator to metal transition and in the closely related colossal magneto-resistance. The pressure tuning of the octahedral distortion gives a unique possibility to separate the basic interactions and, at least in principle, to follow the progressive transformation of a manganite from an intermediate towards a weak electron-phonon coupling regime. Using a diamond anvil cell, temperature and pressure-dependent infrared absorption spectra of La_(0.75)Ca_(0.25)MnO_3 have been collected and, from the spectral weight analysis, the pressure dependence of the insulator to metal transition temperature T_IM has been determined for the first time up to 11.2 GPa. The T_IM(P) curve we proposed to model the present data revealed a universality character in accounting for the whole class of intermediate coupling compounds. This property can be exploited to distinguish the intermediate from the weak coupling compounds pointing out the fundamental differences between the two coupling regimes.Comment: 8 pages, 4 figure

Role of liquid biopsy in oncogene-addicted non-small cell lung cancer

none7noThe discovery of actionable oncogene in non-small cell lung cancer (NSCLC) allowed the identification of a subgroup of patients who benefit from targeted tyrosine kinase inhibitors more than others. Mutations in the epidermal growth factor receptor (EGFR), translocations in the anaplastic lymphoma kinase (ALK) and rearrangements in the ROS proto-oncogene 1 (ROS1) must be identified in tumor tissue to guide the proper treatment choice. Liquid biopsy is based on the analysis of tumor materials released in the circulation. Liquid biopsy can be complementary to tissue biopsy, both at baseline and at progression, especially in the detection of somatic gene alterations emerging during the treatment with tyrosine kinase inhibitors (TKIs). Particularly, circulating DNA is used to find mutations in driver oncogenes, while circulating tumor cells, extracellular vesicles (EVs) and cell-free microRNAs (cfmiRNAs) are still under investigation. To help the unbiased use of liquid biopsy in the choice of the appropriate therapy, some recommendations were delivered by expert panels. Currently, analysis of EGFR mutations in cell-free DNA (cfDNA) is recommended at baseline when tissue biopsy harbors scarce tumor cells, and at progression before performing tissue biopsy; liquid biopsy analysis for other oncogenic drivers is not indicated in the clinical practice.openCanale M.; Pasini L.; Bronte G.; Delmonte A.; Cravero P.; Crino L.; Ulivi P.Canale, M.; Pasini, L.; Bronte, G.; Delmonte, A.; Cravero, P.; Crino, L.; Ulivi, P

Advances in molecular mechanisms and immunotherapy involving the immune cell-promoted epithelial-to-mesenchymal transition in lung cancer

none8noImmunotherapy has offered a new opportunity for the treatment of many malignancies. In patients with lung cancer, immune checkpoint inhibitors have significantly improved survival. However, little is known about predictive factors or primary and acquired resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is a complex of phenotypic changes involved in carcinogenesis and resistance to cancer treatments. Specifically, immune cells in the tumor microenvironment can promote EMT, and mesenchymal phenotype acquisition negatively regulates the anticancer immune response. EMT is associated with higher expression of PD-L1 and other immune checkpoints. In this review, we focused on the role of EMT in the interplay between tumor cells and the immune system, with particular emphasis on lung cancer. On the basis of our findings, we hypothesize that the effects of EMT on immune cells could be overcome in this disease by a new combination of immune checkpoint inhibitors.openDe Matteis S.; Canale M.; Verlicchi A.; Bronte G.; Delmonte A.; Crino L.; Martinelli G.; Ulivi P.De Matteis, S.; Canale, M.; Verlicchi, A.; Bronte, G.; Delmonte, A.; Crino, L.; Martinelli, G.; Ulivi, P

New generation anaplastic lymphoma kinase inhibitors

Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3*7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60-90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting

Raman-like scattering using high energy neutrons: applications to hydrogen and hydrogen-containing materials

The extensive use of Raman spectroscopy in the investigation of the internal molecular motions has been one the most relevant achievements of the last century. Thanks to this experimental technique, thousands of molecular structures have been determined and refined. Nonetheless, the use of photons, mostly in the visible region, has been soon recognized to represent a limiting factor for optically dense materials. The availability of dense beams of high energy neutrons, together with the construction of dedicated spectroscopic instrumentation, has allowed to get rid of this restriction and to take full advantage of the high neutron penetration power in dense matter. Today, the resolving power of neutron instrumentation is not too much dissimilar from that of the corresponding photon instrumentation and the available energy range extends well beyond the eV limit. Thus, allowing to cover the whole vibrational spectrum available to any molecular system. In this contribution, I will show how a dedicated instrument (TOSCA at ISIS) can be effectively used in neutron spectroscopy applications for the investigation of rotovibrational motions in condensed matter systems. Thus becoming an effective aquivalent of a Raman spectrometer, with the invaluable advantage of the neutron penetration power in dense systems. A further advantage of a dedicated high energy neutron spectrometer is represented by the possibility of exploring the application of the Impulse Approximation limit to the center of mass dynamics of molecular systems. By this technique, taking into account the high incoherent neutron scattering cross section of the proton and the extensive energy range available on TOSCA, a wide research area can be exploited allowing to obtain a direct experimental information on the quantum dynamics of liquid and solid bulk hydrogen. Also, it will be shown how the peculiar characteristics of a dedicated neutron Raman instrument can be exploited in the investigation of the quantum dynamics of molecular hydrogen in the nanoconfined geometry of clathrate hydrates, or in detecting its rotational motion on the surface of a carbon nanotube. Last, but not least, important applications of this spectroscopic tool to the investigation of hydrogen-storage materials, including simple and complex light metal hydrides, will be outlined

Liquid biopsy for egfr mutation analysis in advanced non-small-cell lung cancer patients: Thoughts drawn from a real-life experience

none12noBackground: Liquid biopsy analysis for EGFR detection in cell-free DNA (cfDNA) from NSCLC patients has become routine. The aim of this study was to explore its applicability in clinical practice. Methods: We collected data of EGFR-mutated NSCLC patients with liquid biopsy analysis. Data included test timing, concomitant tissue re-biopsy, therapy change, histology, stage, smoking habits, gender and age. All analyses were performed via a real-time PCR method to analyze EGFR mutations at exons 18, 19, 20 and 21. Variant allele frequency was performed for patients with available sequential EGFR mutation analysis in cfDNA. Overall survival was analyzed through the Kaplan–Meier method. We designed flow charts to show the real-life application of liquid biopsy. Results: We found that liquid biopsy is used in treatment-naïve patients as an alternative to EGFR detection in tumor tissue, and in patients with positive or negative EGFR from tumor biopsy. The majority of liquid biopsy analyses were performed in NSCLC patients who were disease progressive during TKI therapy. The presence of EGFR mutation in cfDNA was associated with a worse prognosis. In two patients, VAF of EGFR mutations in cfDNA was concordant with tumor volume changes. Conclusion: These findings suggest that liquid biopsy for EGFR detection can continue to be useful.openUlivi P.; Petracci E.; Canale M.; Priano I.; Capelli L.; Calistri D.; Chiadini E.; Cravero P.; Rossi A.; Delmonte A.; Crino L.; Bronte G.Ulivi, P.; Petracci, E.; Canale, M.; Priano, I.; Capelli, L.; Calistri, D.; Chiadini, E.; Cravero, P.; Rossi, A.; Delmonte, A.; Crino, L.; Bronte, G