From Non-Disjoint Combination to Satisfiability and Model-Checking of Infinite State Systems

In the first part of our contribution, we review recent results on combined constraint satisfiability for first order theories in the non-disjoint signatures case: this is done mainly in view of the applications to temporal satisfiability and model-checking covered by the second part of our talk, but we also illustrate in more detail some case-study where non-disjoint combination arises. The first case deals with extensions of the theory of arrays where indexes are endowed with a Presburger arithmetic structure and a length expressing `dimension\u27 is added; the second case deals with the algebraic counterparts of fusion in modal logics. We then recall the basic features of the Nelson-Oppen method and investigate sufficient conditions for it to be complete and terminating in the non-disjoint signatures case: for completeness we rely on a model-theoretic $T_0$-compatibility condition (generalizing stable infiniteness) and for termination we impose a noetherianity requirement on positive constraints chains. We finally supply examples of theories matching these combinability hypotheses. In the second part of our contribution, we develop a framework for integrating first-order logic (FOL) and discrete Linear time Temporal Logic (LTL). Manna and Pnueli have extensively shown how a mixture of FOL and LTL is sufficient to precisely state verification problems for the class of reactive systems: theories in FOL model the (possibly infinite) data structures used by a reactive system while LTL specifies its (dynamic) behavior. Our framework for the integration is the following: we fix a theory $T$ in a first-order signature $Sigma$ and consider as a temporal model a sequence $cM_1, cM_2, dots$ of standard (first-order) models of $T$ and assume such models to share the same carrier (or, equivalently, the domain of the temporal model to be `constant\u27). Following Plaisted, we consider symbols from a subsignature $Sigma_r$ of $Sigma$ to be emph{rigid}, i.e. in a temporal model $cM_1, cM_2, dots$, the $Sigma_r$-restrictions of the $cM_i$\u27s must coincide. The symbols in $Sigmasetminus Sigma_r$ are called `flexible\u27 and their interpretation is allowed to change over time (free variables are similarly divided into `rigid\u27 and `flexible\u27). For model-checking, the emph{initial states} and the emph{transition relation} are represented by first-order formulae, whose role is that of (non-deterministically) restricting the temporal evolution of the model. In the quantifier-free case, we obtain sufficient conditions for %undecidability and decidability for both satisfiability and model-checking of safety properties emph{by lifting combination methods} for emph{non-disjoint} theories in FOL: noetherianity and $T_0$-compatibility (where $T_0$ is the theory axiomatizing the rigid subtheory) gives decidability of satisfiability, whereas $T_0$-compatibility and local finiteness give safety model-checking decidability. The proofs of these decidability results suggest how decision procedures for the constraint satisfiability problem of theories in FOL and algorithms for checking the satisfiability of propositional LTL formulae can be integrated. This paves the way to employ efficient Satisfiability Modulo Theories solvers in the model-checking of infinite state systems. We illustrate our techniques on some examples and discuss further work in the area

SINEUPs are modular antisense long non-coding RNAs that increase synthesis of target proteins in cells

Despite recent efforts in discovering novel long non-coding RNAs (lncRNAs) and unveiling their functions in a wide range of biological processes their applications as biotechnological or therapeutic tools are still at their infancy. We have recently shown that AS Uchl1, a natural lncRNA antisense to the Parkinson's disease-associated gene Ubiquitin carboxyl-terminal esterase L1 (Uchl1), is able to increase UchL1 protein synthesis at post-transcriptional level. Its activity requires two RNA elements: an embedded inverted SINEB2 sequence to increase translation and the overlapping region to target its sense mRNA. This functional organization is shared with several mouse lncRNAs antisense to protein coding genes. The potential use of AS Uchl1-derived lncRNAs as enhancers of target mRNA translation remains unexplored. Here we define AS Uchl1 as the representative member of a new functional class of natural and synthetic antisense lncRNAs that activate translation. We named this class of RNAs SINEUPs for their requirement of the inverted SINEB2 sequence to UP-regulate translation in a gene-specific manner. The overlapping region is indicated as the Binding Doman (BD) while the embedded inverted SINEB2 element is the Effector Domain (ED). By swapping BD, synthetic SINEUPs are designed targeting mRNAs of interest. SINEUPs function in an array of cell lines and can be efficiently directed toward N-terminally tagged proteins. Their biological activity is retained in a miniaturized version within the range of small RNAs length. Its modular structure was exploited to successfully design synthetic SINEUPs targeting endogenous Parkinson's disease-associated DJ-1 and proved to be active in different neuronal cell lines. In summary, SINEUPs represent the first scalable tool to increase synthesis of proteins of interest. We propose SINEUPs as reagents for molecular biology experiments, in protein manufacturing as well as in therapy of haploinsufficiencies

Identification of novel proteins binding the AU-rich element of \u3b1-prothymosin mRNA through the selection of open reading frames (RIDome)

We describe here a platform for high-throughput protein expression and interaction analysis aimed at identifying the RNA-interacting domainome. This approach combines the selection of a phage library displaying "filtered" open reading frames with next-generation DNA sequencing. The method was validated using an RNA bait corresponding to the AU-rich element of \u3b1-prothymosin, an RNA motif that promotes mRNA stability and translation through its interaction with the RNA-binding protein ELAVL1. With this strategy, we not only confirmed known RNA-binding proteins that specifically interact with the target RNA (such as ELAVL1/HuR and RBM38) but also identified proteins not previously known to be ARE-binding (R3HDM2 and RALY). We propose this technology as a novel approach for studying the RNA-binding proteome

a retrospective study of trifluridine tipiracil in pretreated metastatic colorectal cancer patients in clinical practice

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TRIPLETE: A randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer

FOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective of RAS and BRAF molecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity in RAS and BRAF wild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients with RAS and BRAF wild-type metastatic colorectal cancer. Methods This is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreated RAS and BRAF wild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m 2, oxaliplatin 85 mg/m 2, L-leucovorin 200 mg/m 2, 5-fluoruracil 2400 mg/m 2 48-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5-fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria. Discussion The relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres. Clinical trial information NCT03231722

Surgical Antimicrobial Prophylaxis in Neonates and Children Undergoing Neurosurgery: A RAND/UCLA Appropriateness Method Consensus Study

Pediatric neurosurgery is a highly specialized branch of surgery in which surgical site infections (SSIs) are potentially serious complications that can also adversely affect a good surgical outcome, compromising functional recovery and, in some cases, even putting the patient's life at risk. The main aim of this consensus document is to provide clinicians with a series of recommendations on antimicrobial prophylaxis for neonates and children undergoing neurosurgery. The following scenarios were considered: (1) craniotomy or cranial/cranio-facial approach to craniosynostosis; (2) neurosurgery with a trans-nasal-trans-sphenoidal approach; (3) non-penetrating head injuries; (4) penetrating head fracture; (5) spinal surgery (extradural and intradural); (6) shunt surgery or neuroendoscopy; (7) neuroendovascular procedures. Patients undergoing neurosurgery often undergo peri-operative antibiotic prophylaxis, with different schedules, not always supported by scientific evidence. This consensus provides clear and shared indications, based on the most updated literature. This work has been made possible by the multidisciplinary contribution of experts belonging to the most important Italian scientific societies, and represents, in our opinion, the most complete and up-to-date collection of recommendations on the behavior to be held in the peri-operative setting in this type of intervention, in order to guide physicians in the management of the patient, standardize approaches and avoid abuse and misuse of antibiotics

Prevention of Surgical Site Infections in Neonates and Children: Non-Pharmacological Measures of Prevention

A surgical site infection (SSI) is an infection that occurs in the incision created by an invasive surgical procedure. Although most infections are treatable with antibiotics, SSIs remain a significant cause of morbidity and mortality after surgery and have a significant economic impact on health systems. Preventive measures are essential to decrease the incidence of SSIs and antibiotic abuse, but data in the literature regarding risk factors for SSIs in the pediatric age group are scarce, and current guidelines for the prevention of the risk of developing SSIs are mainly focused on the adult population. This document describes the current knowledge on risk factors for SSIs in neonates and children undergoing surgery and has the purpose of providing guidance to health care professionals for the prevention of SSIs in this population. Our aim is to consider the possible non-pharmacological measures that can be adopted to prevent SSIs. To our knowledge, this is the first study to provide recommendations based on a careful review of the available scientific evidence for the non-pharmacological prevention of SSIs in neonates and children. The specific scenarios developed are intended to guide the healthcare professional in practice to ensure standardized management of the neonatal and pediatric patients, decrease the incidence of SSIs and reduce antibiotic abuse

Oscillation Physics with a Neutrino Factory

A generation of neutrino experiments have established that neutrinos mix and probably have mass. The mixing phenomenon points to processes beyond those of the Standard Model, possibly at the Grand Unification energy scale. A extensive sequence of of experiments will be required to measure precisely all the parameters of the neutrino mixing matrix, culminating with the discovery and study of leptonic CP violation. As a first step, extensions of conventional pion/kaon decay beams, such as off-axis beams or low-energy super-beams, have been considered. These could yield first observations of $\nu_\mu \to \nu_e$ transitions at the atmospheric frequency, which have not yet been observed, and a first measurement of $\theta_{13}$. Experiments with much better flux control can be envisaged if the neutrinos are obtained from the decays of stored particles. One such possibility is the concept of beta beams provided by the decays of radioactive nuclei, that has been developed within the context of these studies. These would provide a pure (anti-)electron-neutrino beam of a few hundred MeV, and beautiful complementarity with a high-intensity, low-energy conventional beam, enabling experimental probes of T violation as well as CP violation. Ultimately, a definitive and complete set of measurements would offered by a Neutrino Factory based on a muon storage ring. This powerful machine offers the largest reach for CP violation, even for very small values of $\theta_{13}$