Clinical, morphological and molecular characterization of cancer phenotypes associated with chronic obstructive pulmonary disease (COPD): new prospective of target therapies

BACKGROUND Chronic obstructive pulmonary disease (COPD) and lung cancer are two catastrophic diseases, representing leading causes of morbidity and mortality worldwide. Although the treatment has greatly improved both diseases continue to show increasing frequency and above all an unpredictable progression. Several studies have firmly established a strict connection between COPD and lung cancer highlighting also the importance of the inflammatory response as a risk factor for both diseases. The inflammatory paradigm is undoubtedly one of the most fascinating theories to connect COPD and lung cancer and it has acquired new impetus by the recent discoveries in the COPD pathogenesis. Emerging evidence in this context has emphasized the role of adaptive immune responses, possibly with an autoimmune component due to the recognition of pulmonary selfantigens modified by cigarette smoking and to the failure of mechanisms regulating immunological tolerance. In this context, COPD-associated cancers might have specific pathogenetic and morphological features, differently from tumours arising in non-COPD patients, due to the synergic effect of cigarette smoke and chronic inflammation. AIM OF THE RESEARCH This research project focuses on the study of lung cancer in patients with COPD compared to smokers without COPD and never smoker patients in order to identify eventual distinct clinical, morphological and molecular phenotypes. MATERIALS AND METHODS From 2010 to 2012, we prospectively enrolled patients with peripheral non small lung cancer submitted to anatomical lung resection (lobectomy, bilobectomy or pneumonectomy) associated with systematic lymphadenectomy. Patients with central airway cancer, secondary lung tumours or previously submitted to inductive treatment were excluded from the study. According to respiratory functional tests and smoking history patients were then divided in 3 groups: COPD patients, smokers without COPD and never-smoker subjects with normal lung function (FEV1/FVC ratio >70%). Each patient underwent a full clinical and instrumental assessment. Morphological studies included detailed analysis of growth pattern (according to the latest revision of adenocarcinoma classification), cell proliferation (Ki67/MIB1 expression), parameters of intra-and peri-tumoral remodelling (inflammation, fibrosis and necrosis) and tumoural detection of interleukin-17 (IL-17) cytokine. Genetic analysis of EGFR and KRAS mutations was also performed in all cases. RESULTS In the study period, 66 patients who met the inclusion/exclusion criteria were initially enrolled:16 COPD, 32 smokers without COPD and 18 never smokers. As the selection criteria affected the predominant histologic profile with a clear predominance of the adenocarcinoma histotype (63% in COPD patients, 71% in smokers and 56% in neversmokers), we performed our investigations only in patients with this histology to obtain results not affected by different histotypes. Therefore the study group was composed of 43 patients (10 COPD, 23 smokers and 10 never-smokers), whose main demographic and functional parameters were comparable except for male/female ratio, reversed in never-smokers, and for lung function, reduced in COPD patients, as expected. Given the specific aim the comparison of different clinical, morphological and molecular data was mainly performed within the category of smoking patients (COPD patients and smokers without COPD), while never smokers represented control group. From a clinical point of view the most important differences concern the number of peripheral blood basophils and standard uptake value of positron emission tomography–computed tomography (SUV of PET-CT). COPD patients showed a significant higher number of basophils and lower SUV of PET-CT than smokers without COPD. Concerning the histological evaluation adenocarcinoma of COPD patients showed a more frequent lepid pattern, less evident solid aspect and lower MIB1/Ki67 index than adenocarcinoma of smokers without COPD. A significant more extensive necrosis was found in adenocarcinoma of COPD and smokers without COPD compared to never-smokers. Finally although not statistically significant a stronger IL17 tissue expression was observed in COPD cases compared to smokers without COPD. As regards molecular data the most interesting finding was a trend of less frequency of KRAS mutation in adenocarcinoma of COPD patients. CONCLUSIONS Adenocarcinoma in COPD patients presents clinical, molecular and morphological features of lower aggressiveness (higher number of basophils, low SUV of PET-CT, increased lepidic component, reduced solid pattern, lower cell proliferation and less frequent K-RAS mutation) compared to that of smokers without COPD. Alternative mechanisms of carcinogenesis may be involved in the development/progression of lung cancer in COPD patients. Given the importance of inflammation in the pathogenesis of the disease other mechanisms, such as IL-17 pathway, mainly driving inflammatory mediated carcinogenesis might be crucial. Additional knowledge of these mechanisms would be of considerable help in the fight against lung cancer especially concerning therapeutic perspectives, providing a rational basis for the development of targeted and more effective treatments

Mar-Co: a new dependence structure to model match outcomes in football

The approaches commonly used to model the number of goals in a football match are characterised by strong assumptions about the dependence between the number of goals scored by the two competing teams and about their marginal distribution. In this work, we argue that the assumptions traditionally made are not always based on solid arguments and sometimes they can be hardly justified. In light of this, we propose a modification of the Dixon and Coles (1997) model by relaxing the assumption of Poisson-distributed marginal variables and by introducing an innovative dependence structure. Specifically, we define the joint distribution of the number of goals scored during a match by means of thoroughly chosen marginal (Mar-) and conditional distributions (-Co). The resulting Mar-Co model is able to balance flexibility and conceptual simplicity. A real data application involving five European leagues suggests that the introduction of the novel dependence structure allows to capture and interpret fundamental league-specific dynamics. In terms of betting performance, the newly introduced Mar-Co model does not perform worse than the Dixon and Coles one in a traditional framework (i.e. 1-X-2 bet) and it outperforms the competing model when a more comprehensive dependence structure is needed (i.e. Under/Over 2.5 bet)

Single and Double Knockouts of the Genes for Photosystem I Subunits G, K, and H of Arabidopsis

Photosystem I (PSI) of higher plants contains 18 subunits. Using Arabidopsis En insertion lines, we have isolated knockout alleles of the genes psaG, psaH2, and psaK, which code for PSI-G, -H, and -K. In the mutants psak-1 and psag-1.4, complete loss of PSI-K and -G, respectively, was confirmed, whereas the residual H level in psah2-1.4 is due to a second gene encoding PSI-H, psaH1. Double mutants, lacking PSI-G, and also -K, or a fraction of -H, together with the three single mutants were characterized for their growth phenotypes and PSI polypeptide composition. In general, the loss of each subunit has secondary, in some cases additive, effects on the abundance of other PSI polypeptides, such as D, E, H, L, N, and the light-harvesting complex I proteins Lhca2 and 3. In the G-less mutant psag-1.4, the variation in PSI composition suggests that PSI-G stabilizes the PSI-core. Levels of light-harvesting complex I proteins in plants, which lack simultaneously PSI-G and -K, indicate that PSI subunits other than G and K can also bind Lhca2 and 3. In the same single and double mutants, psag-1.4, psak-1, psah2-1.4, psag-1.4/psah2-1.4, and psag-1.4/psak-1 photosynthetic electron flow and excitation energy quenching were analyzed to address the roles of the various subunits in P700 reduction (mediated by PSI-F and -N) and oxidation (PSI-E), and state transitions (PSI-H). Based on the results, we also suggest for PSI-K a role in state transitions

Interference at the Single Photon Level Along Satellite-Ground Channels

Quantum interference arising from superposition of states is a striking evidence of the validity of Quantum Mechanics, confirmed in many experiments and also exploited in applications. However, as for any scientific theory, Quantum Mechanics is valid within the limits in which it has been experimentally verified. In order to extend such limits, it is necessary to observe quantum interference in unexplored conditions such as moving terminals at large distance in Space. Here we experimentally demonstrate single photon interference at a ground station due to the coherent superposition of two temporal modes reflected by a rapidly moving satellite thousand kilometers away. The relative speed of the satellite induces a varying modulation in the interference pattern. The measurement of the satellite distance in real time by laser ranging allowed us to precisely predict the instantaneous value of the interference phase. We then observed the interference patterns with visibility up to $67\%$ with three different satellites and with path length up to 5000 km. Our results attest the viability of photon temporal modes for fundamental tests of Physics and Quantum Communications in Space.Comment: Version accepted for publication in Phys. Rev. Let

Ex-vivo recruitment and x-ray assessment of donor lungs in a challenging retrieval from a donor supported by lvad using the portable normothermic perfusion system: A case report

Lung transplantation (LTx) is limited by the shortage of suitable donors. To overcome this problem, many programs have begun to use donors with extended criteria (marginal donors). However, brain-dead patients with implanted mechanical circulatory support system have rarely been considered as potential lung donors. This case demonstrates the feasibility of lung transplantations from organ donors supported by a mechanical circulatory support system despite the possible difficulties of lung retrieval. CASE PRESENTATION: Our case presents a successful procurement and bilateral lung transplantation from a donor supported by a left ventricular assist device (LVAD) who experienced an intraoperatively haemodynamic complication. The use of portable normothermic perfusion device let us to reduce ischemic injury and assess these marginal donor lungs helping us to determine the clinical suitability for transplantation. Given our extensive experience with the device instrumentation and management, the EVLP process was uneventful with excellent post-transplant course. CONCLUSIONS: This case report demonstrates the feasibility of lung transplantations from organ donors supported by a mechanical circulatory support system using the portable normothermic perfusion platform to assess and preserve these donor lungs

Extending Wheeler's delayed-choice experiment to Space

Gedankenexperiments have consistently played a major role in the development of quantum theory. A paradigmatic example is Wheeler's delayed-choice experiment, a wave-particle duality test that cannot be fully understood using only classical concepts. Here, we implement Wheeler's idea along a satellite-ground interferometer which extends for thousands of kilometers in Space. We exploit temporal and polarization degrees of freedom of photons reflected by a fast moving satellite equipped with retro-reflecting mirrors. We observed the complementary wave-like or particle-like behaviors at the ground station by choosing the measurement apparatus while the photons are propagating from the satellite to the ground. Our results confirm quantum mechanical predictions, demonstrating the need of the dual wave-particle interpretation, at this unprecedented scale. Our work paves the way for novel applications of quantum mechanics in Space links involving multiple photon degrees of freedom.Comment: 4 figure

Poly(borosiloxanes) as precursors for carbon fiber ceramic matrix composites

Ceramic matrix composites (CMCs), constituted of a silicon boron oxycarbide (SiBCO) matrix and unidirectional carbon fiber rods as a reinforcement phase, were prepared by pyrolysis of carbon fiber rods wrapped in polysiloxane (PS) or poly(borosiloxane) (PBS) matrices. The preparation of the polymeric precursors involved hydrolysis/condensation reactions of alkoxysilanes in the presence and absence of boric acid, with B/Si atomic ratios of 0.2 and 0.5. Infrared spectra of PBS showed evidence of Si-O-B bonds at 880 cm-1, due to the incorporation of the crosslinker trigonal units of BO3 in the polymeric network. X ray diffraction analyses exhibited an amorphous character of the resulting polymer-derived ceramics obtained by pyrolysis up to 1000 °C under inert atmosphere. The C/SiBCO composites showed better thermal stability than the C/SiOC materials. In addition, good adhesion between the carbon fiber and the ceramic phase was observed by SEM microscopy147151Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Surgical and neurologic outcomes after robotic thymectomy in 100 consecutive patients with myasthenia gravis

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