New Advances in Liquid Biopsy Technologies for Anaplastic Lymphoma Kinase (ALK)—Positive Cancer

Cancer cells are characterized by high genetic instability, that favors tumor relapse. The identification of the genetic causes of relapse can direct next-line therapeutic choices. As tumor tissue rebiopsy at disease progression is not always feasible, noninvasive alternative methods are being explored. Liquid biopsy is emerging as a non-invasive, easy and repeatable tool to identify specific molecular alterations and monitor disease response during treatment. The dynamic follow-up provided by this analysis can provide useful predictive information and allow prompt therapeutic actions, tailored to the genetic profile of the recurring disease, several months before radiographic relapse. Oncogenic fusion genes are particularly suited for this type of analysis. Anaplastic Lymphoma Kinase (ALK) is the dominant driver oncogene in several tumors, including Anaplastic Large-Cell Lymphoma (ALCL), Non-Small Cell Lung Cancer (NSCLC) and others. Here we review recent findings in liquid biopsy technologies, including ctDNA, CTCs, exosomes, and other markers that can be investigated from plasma samples, in ALK-positive cancers

Baku Memorial Park 2021

Il progetto consiste in un memoriale delle guerre combattute nella regione azerbaijana del Nagorno Karaback. Il progetto, seguendo le linee metodologiche contenute nel programma ricevuto, vuole interpretare la identità azera basandosi principalmente sulla antica tradizione dei tappeti, espressione di una cultura visiva in cui convergono motivi geometrici e figurativi di straordinario fascino, universalmente ammirati anche per il valore simbolico. Il master plan del Memorial si compone di quattro episodi che cercano nel loro insieme di realizzare una specie di racconto che rievoca gli eventi delle due guerre recenti e ricorda ai visitatori i nomi delle vittime incisi su delle grandi lapidi di pietra disposte lungo percorsi. Il primo episodio è l’arco di ingresso dal quale si diramano percorsi in quattro direzioni. L’edificio è concepito in muratura di pietra locale in modo da ricordare i monumenti del centro storico che costituiscono nel loro complesso il “cuore antico” della città. Il motivo centrale dell’arco deriva dalla analisi strutturale dei tappeti denominati “Chelebi” o “Chelabard”, dal nome di un villaggio del Caucaso, tipici della regione del Lagorno Karaback dei quali il programma consegnatoci conteneva delle immagini di grande suggestione. Il secondo episodio è costituito da un complesso insieme scultoreo e architettonico che avrà il compito , nella sua configurazione avveniristica, di celebrare il futuro della nazione azera che si presenta oggi , nello scenario mondiale, come un grande esempio di sviluppo sia in campo politico che architettonico, potendo vantare la crescente bellezza di una capitale, come Baku in continua trasformazione che, per mantenendo un alto grado di vivibilità, ha acquistato , negli ultimi decenni un volto decisamente moderno e può vantare già alcuni capolavori della architettura del XXI secolo. Il terzo episodio è caratterizzato da un a grande fontana posta al centro di uno specchio d’acqua che riproduce un altro dei tipici motivi centrali dei tappeti azeri, la cosiddetta “Lezghi star”, che deriva da un motivo diffuso nei pavimenti romani. Dovrebbe questo luogo festoso indicare il superamento dei conflitti e l’augurio di una pace duratura. Potrebbero arricchirlo - ove si ritenesse utile - spazi di gioco riservato ai bambini. Il quarto episodio è il museo, contenuto, come una piccola città, all’interno di un recinto murario, dal quale emergono le sagome dei volumi edilizi che ospiteranno la documentazione relativa alle vicende dei due conflitti recenti. I volumi di forme, materiali e colori differenti -che testimoniano la diversità e la complessità delle figure che popolano una città- sono collocati secondo un ordine geometrico all’interno del recinto e saranno collegati da percorsi coperti e da patii arricchiti da specchi d’acqua, alberi e sculture. Per quanto riguarda la rogettazione paesaggistica degli arbusti e degli alberi prevista dal Masterplan, le tre aree dell'Arco d'ingresso, del Memoriale e della Fontana saranno protette da due cinture perimetrali di alberi ad alto fusto. Gli alberi progettati hanno la funzione di abbracciare e difendere la parte centrale del grande giardino dai rumori delle arterie stradali. L'etimologia della parola Giardino (originariamente Paràdeisos) è legata ad un recinto. Le due aree boschive marginali sono immaginate come attraversate da piccoli percorsi pedonali, come se fossero una rete erbosa che collega "l'Albero della Vita" e gli altri elementi architettonici del Complesso della Memoria, dove passeggiare all'ombra degli alberi. L'accessibilità al Complesso dovrà essere garantita da un parcheggio pianeggiante a lato dell'area museale nonché dalla realizzazione di un parcheggio interrato in corrispondenza dell'Arco d'ingresso.The project is a Memorial of the Wars fought in the region of Karabakh (Qarabağ) in Azerbaijan. The Project, following the methodological lines contained in the Preliminary Program received, interprets the Azerbaijani cultural identity following the ancient tradition of carpets. This is the expression of a visual culture in which geometric and figurative motifs of extraordinary charm converge, universally admired also for their symbolic value. The Memorial Master Plan consists of four episodes that create a sort of visual narrative commemorating the main events of the two recent Wars. Large vertical marble plates placed along the pedestrian paths will remind the visitors of the victims’ names engraved there. The first episode is the Entrance Arch from which the main routes branch off in four directions. The building is designed in local stone masonry in order to recall the monuments of the Old City center which together constitute the “ancient heart” of the capital. The central motif of the Arch derives from the geometrical analysis of the carpets called “Chelebi”, from the name of a village in the Caucasus, typical of the Karabakh region, with highly powerful images as indicated in the Program delivered to us. The second episode consists of a complex sculptural and architectural ensemble that will have the task, in its futuristic configuration, of celebrating the future of the Azerbaijani Nation that presents itself today, in the world scenario, as a great example of development both in the political and architectural fields. The growing beauty of Baku is in continuous transformation, but maintaining a high degree of life quality and, in recent decades, it has acquired a decidedly modern look and can already boast some of the masterpieces of the twenty-first century architecture. The third episode is characterized by a large Fountain placed in the center of a water pool that reproduces another of the typical central motifs of Azerbaijani carpets, the so-called “Lezghi star”, which derives from an Hellenistic motif common in ancient Roman floors. This festive place should indicate the overcoming of conflicts and the wish for everlasting Peace. It could be possibly enriched by playgrounds reserved for children. The fourth episode is the Museum within a wall enclosure, from which the silhouettes of the building volumes emerge. Like a small fortified town, the enclosure will house the documentation relating to the events of the two recent conflicts. The volumes of different shapes, materials and colors - which testify the diversity and complexity of the figures that populate a City - are placed according to a geometric order within the enclosure and will be connected by covered paths and patios enriched by ponds, trees and sculptures. The different small buildings proposed in the Preliminary Project want to allude to a series of autonomous environments, connected by a straight classical Portico, which can accommodate the various exhibition functions: library, permanent and temporary exhibitions of memorabilia and works of art, open and secluded spaces for virtual reality set-ups. Regarding the Landscape Design of the shrubs and trees envisaged in the Master Plan, the three areas of the Entrance Arch, the Memorial and the Fountain will be protected by two boundary belts of tall trees. The planned trees have the function of embracing and defending the central part of the large garden from the noise of the road arteries. The etymology of the word Garden (originally Paràdeisos) is related to an enclosure. The two marginal wood areas are imagined to be crossed by small pedestrian paths, as if they were a net of grass that connect "the Tree of Life" and the other architectural elements of the Memorial Complex, where you can walk under the shade of the trees. Accessibility to the Complex should be guaranteed by a level car park beside the Museum area as well as by planning an underground car park where the Entrance Arch is located

Synthesis and characterization of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide-based compounds targeting the PA-PB1 interface of influenza A virus polymerase

Influenza viruses (Flu) are responsible for seasonal epidemics causing high rates of morbidity, which can dramatically increase during severe pandemic outbreaks. Antiviral drugs are an indispensable weapon to treat infected people and reduce the impact on human health, nevertheless anti-Flu armamentarium still remains inadequate. In search for new anti-Flu drugs, our group has focused on viral RNA-dependent RNA polymerase (RdRP) developing disruptors of PA-PB1 subunits interface with the best compounds characterized by cycloheptathiophene-3-carboxamide and 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide scaffolds. By merging these moieties, two very interesting hybrid compounds were recently identified, starting from which, in this paper, a series of analogues were designed and synthesized. In particular, a thorough exploration of the cycloheptathiophene-3-carboxamide moiety led to acquire important SAR insight and identify new active compounds showing both the ability to inhibit PA-PB1 interaction and viral replication in the micromolar range and at non-toxic concentrations. For few compounds, the ability to efficiently inhibit PA-PB1 subunits interaction did not translate into anti-Flu activity. Chemical/physical properties were investigated for a couple of compounds suggesting that the low solubility of compound 14, due to a strong crystal lattice, may have impaired its antiviral activity. Finally, computational studies performed on compound 23, in which the phenyl ring suitably replaced the cycloheptathiophene, suggested that, in addition to hydrophobic interactions, H-bonds enhanced its binding within the PAC cavity

Accounting for Target Flexibility and Water Molecules by Docking to Ensembles of Target Structures: The HCV NS5B Palm Site I Inhibitors Case Study

The introduction of new anti-HCV drugs in therapy is an imperative need and is necessary with a view to develop an interferon-free therapy. Thus, the discovery and development of novel small molecule inhibitors of the viral NS5B polymerase represent an exciting area of research for many pharmaceutical companies and academic groups. This study represents a contribution to this field and relies on the identification of the best NS5B model(s) to be used in structure-based computational approaches aimed at identifying novel non-nucleoside inhibitors of one of the protein allosteric sites, namely, palm site I. First, the NS5B inhibitors at palm site I were classified as water-mediated or nonwater-mediated ligands depending on their ability to interact with or displace a specific water molecule. Then, we took advantage of the available X-ray structures of the NS5B/ligand complexes to build different models of protein/water combinations, which were used to investigate the influence on docking studies of solvent sites as well as of the influence of the protein conformations. As the overall trend, we observed improved performance in the docking results of the water-mediated inhibitors by inclusion of explicit water molecules, with an opposite behavior generally happening for the nonwater-mediated inhibitors. The best performing target structures for the two ligand sets were then used for virtual screening simulations of a library containing the known NS5B inhibitors along with related decoys to assess the best performing targets ensembles on the basis of their ability to discriminate active and inactive compounds as well as to generate the correct binding modes. The parallel use of different protein structures/water sets outperformed the use of a single target structure, with the two-protein 3H98/2W-2FVC/7W and 3HKY/NoW-3SKE/NoW models resulting in the best performing ensembles for water-mediated inhibitors and nonwater-mediated inhibitors, respectively. The information gathered from this work confirms the primary role of water molecules and protein flexibility in docking-based studies and can be exploited to aid NS5B-directed HCV drug discovery efforts

New pan-ALK inhibitor-resistant EML4::ALK mutations detected by liquid biopsy in lung cancer patients

Abstract ALK and ROS1 fusions are effectively targeted by tyrosine kinase inhibitors (TKIs), however patients inevitably relapse after an initial response, often due to kinase domain mutations. We investigated circulating DNA from TKI-relapsed NSCLC patients by deep-sequencing. New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinical and 2 investigational TKIs

Ecosistemi da progettare. Esercizi progettuali per la conservazione della biodiversit\ue0, il ripristino funzionale degli ecosistemi e l\u2019accessibilit\ue0 alle risorse naturali.

In un\u2019epoca di grande pressione sugli ecosistemi naturali, l\u2019uso del territorio per la conservazione della biodiversit\ue0, il recupero funzionale degli ecosistemi pi\uf9 degradati e di sistemi produttivi che si coniughino alle esigenze di biodiversit\ue0, hanno un ruolo strategico di primaria importanza per assicurare la sostenibilit\ue0 delle risorse. La biodiversit\ue0 \ue8 tutto ci\uf2 che abbiamo. Biodiversit\ue0 \ue8 ossigeno, cibo, medicine, risorse economiche, resilienza e adattamento ai cambiamenti naturali, cos\uec come a quelli indotti dalle attivit\ue0 umane. Un mondo senza uccelli, insetti, prati, aree umide o boschi non sosterebbe la popolazione umana esistente, e certamente non renderebbe possibile la ripresa economica che tutti ci auspichiamo. Abbiamo chiesto agli studenti del corso di \u201cEcosistemi, habitat protetti e ripristini ambientali\u201d della Laurea Magistrale in \u201cProgettazione e gestione degli ecosistemi agro-territoriali, forestali e del paesaggio\u201d dell\u2019Alma Mater Studiorum, Universit\ue0 degli Studi di Bologna, di fare un esercizio teorico-pratico sulla base di questa prospettiva e cio\ue8 di elaborare progetti di ripristino ambientale, conservazione della natura, e uso sostenibile delle risorse. Gli studenti hanno risposto con grande seriet\ue0 ed entusiasmo a questa proposta formativa. Sono loro gli ideatori, interlocutori e anche i beneficiari dei progetti che vengono presentati in questo booklet. In alcuni casi hanno ritenuto opportuno coinvolgere la cittadinanza e le associazioni di volontariato locali per poter sviluppare i loro progetti sulla base delle esigenze dei fruitori di queste aree. Queste sono vere e proprie azioni di Citizen Science che integrano l\u2019uso sostenibile dell\u2019ambiente con le esigenze economiche e della societ\ue0, e forniscono una prova della professionalit\ue0 acquisita dai ragazzi in questo percorso. Nell\u2019elaborazione dei progetti i ragazzi sono stati affiancati e stimolati da esperti e professionisti di vari settori che hanno permesso di indirizzare l\u2019esercizio teorico necessario per il sostenimento dell\u2019esame alle esigenze specifiche e attuali dei territori studiati. Con questo booklet desideriamo far conoscere agli addetti ai lavori, enti di gestione, aree protette, comuni, regioni, ai proprietari delle aree scelte come modello per l\u2019esercizio progettuale e alla cittadinanza, i progetti sviluppati nei loro territori. Possono servire come spunto per la pianificazione e la gestione dei territori specifici, ma esprimono anche la necessit\ue0 dei nostri ragazzi di un ambiente fatto di natura e biodiversit\ue0