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Approximately 10–20% of patients with non–small-cell lung cancer (NSCLC) harbor an epidermal growth factor receptor (EGFR) [...]

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16—OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation.

Histiocytic sarcoma is a rare malignant neoplasm arising most commonly in lymph nodes, intestinal tract, skin and soft tissue. The incidence of primary CNS histiocytic sarcoma is even rarer with a total of just 27 cases reported in the literature so far. Herein we describe the first autopsy case of histiocytic sarcoma presenting as a diffuse leptomeningeal disease in absence of a CNS tumor-forming parenchymal lesion. The clinical, pathological and immunophenotypic features are described and an updated literature review on primary CNS histiocytic sarcoma is included.

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16—OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation.

Neurons extend and retract dynamically their neurites during development to form complex morphologies and to reach out to their appropriate synaptic partners. Their capacity to undergo structural rearrangements is in part maintained during adult life when it supports the animal’s ability to adapt to a changing environment or to form lasting memories. Nonetheless, the signals triggering structural plasticity and the mechanisms that support it are not yet fully understood at the molecular level. Here, we focus on the nervous system of the fruit fly to ask to which extent activity modulates neuronal morphology and connectivity during development. Further, we summarize the evidence indicating that the adult nervous system of flies retains some capacity for structural plasticity at the synaptic or circuit level. For simplicity, we selected examples mostly derived from studies on the visual system and on the mushroom body, two regions of the fly brain with extensively studied neuroanatomy.

Mutations in genes encoding several basal lamina components as well as their cellular receptors disrupt normal deposition and remodeling of the cortical basement membrane resulting in a disorganized cerebral and cerebellar cortex. The α6 integrin was the first α subunit associated with cortical lamination defects and formation of neural ectopias. In order to understand the precise role of α6 integrin in the central nervous system (CNS), we have generated mutant mice carrying specific deletion of α6 integrin in neuronal and glia precursors by crossing α6 conditional knockout mice with Nestin-Cre line. Cerebral cortex development occurred properly in the resulting α6 (fl/fl;nestin-Cre) mutant animals. Interestingly, however, cerebellum displayed foliation pattern defects although granule cell (GC) proliferation and migration were not affected. Intriguingly, analysis of Bergmann glial (BG) scaffold revealed abnormalities in fibers morphology associated with reduced processes outgrowth and altered actin cytoskeleton. Overall, these data show that α6 integrin receptors are required in BG cells to provide a proper fissure formation during cerebellum morphogenesis.

Aim: To assess the role of Notch activation in predicting bevacizumab efficacy in colorectal cancer (CRC). Materials & methods: Notch activation was evaluated by immunohistochemistry (IHC) on 65 CRC enrolled within randomized clinical trials assessing first-line bevacizumab-based chemotherapy and on 21 CRC treated with chemotherapy alone. Results: Strong Notch (IHC 3+) activation was negatively associated with response (18 vs 62% in low Notch cases [IHC 0, 1, 2+]; p = 0.016), progression-free survival (4.9 vs 12.1 months; p = 0.002) and overall survival (19.3 vs 30.4 months; p = 0.039). No correlation was found between Notch activation and clinical outcome in CRC treated with chemotherapy alone. Conclusion: A potential role of Notch activation in the antitumor activity of bevacizumab could be hypothesized.

RNA binding proteins assemble on mRNAs to control every single step of their life cycle, from nuclear splicing to cytoplasmic localization, stabilization or translation. Consistent with an essential role of RNA binding proteins in neuronal maturation and function, mutations in this class of proteins, in particular in members of the hnRNP family, have been associated with neurological diseases. To date, however, the physiological function of hnRNPs during in vivo neuronal development has remained poorly explored. Here, we have investigated the role of Drosophila Hrp48, a fly homologue of mammalian hnRNP A2/B1, during central nervous system development. Using a combination of mutant conditions, we showed that hrp48 is required for the formation, growth and guidance of axonal branches in Mushroom Body neurons. Furthermore, our results revealed that hrp48 inactivation induces an overextension of Mushroom Body dorsal axonal branches, with a significantly higher penetrance in females than in males. Finally, as demonstrated by immunolocalization studies, Hrp48 is confined to Mushroom Body neuron cell bodies, where it accumulates in the cytoplasm from larval stages to adulthood. Altogether, our data provide evidence for a crucial in vivo role of the hnRNP Hrp48 in multiple aspects of axon guidance and branching during nervous system development. They also indicate cryptic sex differences in the development of sexually non-dimorphic neuronal structures.

X-ray Computed Tomography (CT) is a well known diagnostic technique. However, it could be very complex if one wants to use it in fields other than medicine. When CT is applied to large objects, as in cultural heritage, several thousand digital images have to be elaborated, operation that takes a long time. As it is not possible to leave the measurement stage near a monument or in a museum for a long time, it is necessary to develop fast image reconstruction software to allow the experimenters to “look inside” the objects quickly in order to repeat the measurements, if necessary, in a more suitable condition before dismantling the equipment. The X-Ray Imaging Group (University of Bologna) has developed several systems for CT of large objects and, recently, a software, for fast image elaboration, that operates on a network of computers. For illustrating the power of our computing system, this presentation will discuss the CT (done in 2008) of a large Japanese wooden statue (over 200cm of height) of the XIII century, located at the royal palace “La Venaria Reale” (Turin). To investigate the entire statue volume, up to 36 scans were necessary and for each of them 720 radiographs were acquired. To reconstruct all the slices of the complete volume of the object (120 GB) it took 20 days of computing on a good standard PC. The parallelization work was done using the Microsoft (Redmond) HPC cluster and thereafter on a new, transportable, 32 cores cluster at the INFN of Bologna. The HPC environment has proven to be dramatically powerful and easy to use allowing to have the results very quickly. A superlinear speedup of 75 was reached with a 32 cores cluster (the speed up factor, 75, is higher than the number of cores, 32).

The functional variety in neuronal composition of an adult brain is established during development. Recent studies proposed that interactions between genetic intrinsic programs and external cues are necessary to generate proper neural diversity [1]. However, the molecular mechanisms underlying this developmental process are still poorly understood. Three main subtypes of Drosophila mushroom body (MB) neurons are sequentially generated during development and provide a good example of developmental neural plasticity [2]. Our present data propose that the environmentally controlled steroid hormone ecdysone functions as a regulator of early-born MB neuron fate during larval-pupal transition. We found that the BTB-zinc finger factor Chinmo acts upstream of ecdysone signaling to promote a neuronal fate switch. Indeed, Chinmo regulates the expression of the ecdysone receptor B1 isoform to mediate the production of γ and α'β' MB neurons. In addition, we provide genetic evidence for a regulatory negative feedback loop driving the α'β' to αβ MB neuron transition in which ecdysone signaling in turn controls microRNA let-7 depression of Chinmo expression. Thus, our results uncover a novel interaction in the MB neural specification pathway for temporal control of neuronal identity by interplay between an extrinsic hormonal signal and an intrinsic transcription factor cascade.

The morphology and the connectivity of neuronal structures formed during early development must be actively maintained as the brain matures. Although impaired axon stability is associated with the progression of various neurological diseases, relatively little is known about the factors controlling this process. We identified Brain tumor (Brat), a conserved member of the TRIM-NHL family of proteins, as a new regulator of axon maintenance inDrosophilaCNS. Brat function is dispensable for the initial growth of Mushroom Body axons, but is required for the stabilization of axon bundles. We found that Brat represses the translation ofsrc64B, an upstream regulator of a conserved Rho-dependent pathway previously shown to promote axon retraction. Furthermore,bratphenotypes are phenocopied bysrc64Boverexpression, and partially suppressed by reducing the levels ofsrc64Bor components of the Rho pathway, suggesting thatbratpromotes axon maintenance by downregulating the levels of Src64B. Finally, Brat regulates brain connectivity via its NHL domain, but independently of its previously described partners Nanos, Pumilio, and d4EHP. Thus, our results uncover a novel post-transcriptional regulatory mechanism that controls the maintenance of neuronal architecture by tuning the levels of a conserved rho-dependent signaling pathway.

During cerebral cortex development, post-mitotic neurons interact with radial glial fibers and the extracellular environment to migrate away from the ventricular region and form a correct laminar structure. Integrin receptors are major mediators of cell-cell and cell-extracellular matrix interactions. Several integrin heterodimers are present during formation of the cortical layers. The alpha5beta1 receptor is expressed in the neural progenitors of the ventricular zone during cerebral cortex formation. Using in utero electroporation to introduce short hairpin RNAs in the brain at embryonic day 15.5, we were able to inhibit acutely the expression of alpha5 integrin in the developing cortex. The knockdown of alpha5 integrin expression level in neural precursors resulted in an inhibition of radial migration, without perturbing the glial scaffold. Moreover, the same inhibitory effect on neuronal migration was observed after electroporation of a Cre recombinase expression plasmid into the neural progenitors of conditional knockout mice for alpha5 integrin. In both types of experiments, the electroporated cells expressing reduced levels of alpha5 integrin accumulated in the premigratory region with an abnormal morphology. At postnatal day 2, ectopic neurons were observed in cortical layer V, while a deficit of neurons was observed in cortical layer II-IV. We show that these neurons do not express a layer V-specific marker, suggesting that they have not undergone premature differentiation. Overall, these results indicate that alpha5beta1 integrin functions in the regulation of neural morphology and migration during cortical development, playing a role in cortical lamination.

The urogenital system can be divided into two functionally different units, the urinary system and the reproductive system, which are nonetheless closely related in terms not only of anatomy but also of embryology. In fact both develop from the same primitive cell mass, the intermediate mesoderm situated along the posterior wall of the abdominal cavity, and the excretory ducts of both systems initially have a common outlet, the cloaca. Despite their close relationship, it would appear opportune to treat them separately.

The phenomenon of cycle slipping in a first-order phase-locked loop is reconsidered and a simple expression for the expected number ? of cycles slipped per second is given in the form of a rapidly converging series. In this way the computation of ? becomes much easier than with previously known formulas. A formula allowing the computation of the expected number of cycles gained or lost per second is also given. These results are obtained by extending a technique used by Viterbi. The outcome of experimental verifications of the theory is also reported.

Una riflessione sulla debolezza della satira attuale: per quanto online sia estremamente diffusa, e spesso perseguitata, la satira contemporanea non incide nel cambiamento di prospettiva sugli eventi e sulle situazioni, bensì conferma la tendenza attuale alla polarizzazione delle posizioni su questioni politiche, sociali, culturali; l'articolo riflette quindi sulla necessità che la satira sposti il suo bersaglio cercando di colpire l'economia, solo in tal caso, ed è l'ipotesi del saggio, una satira può far comprendere la radice di un problema collettivo e scardinare i meccanismi di polarizzazione del dibattito attuale.

Il quidditch è uno sport ideato da J.K. Rowling per le avventure di Harry Potter. I lettori ne hanno però ideato una versione per non maghi (babbani) che sta ora conquistando un significativo numero di giocatori nel mondo, tanto che sono sorte leghe nazionali e internazionali dello sport, e sono stati organizzati anche mondiali di quidditch. Nel 2018 il mondiale si è svolto in Italia, e ha portato attenzione mediatica a questo nuovo sport, di cui l'intervento ricostruisce le vicende che l'hanno portato dal testo letterario (analizzandone le caratteristiche e comparandole con l'adattamento cinematografico) ai campi da gioco, ponendo attenzione al ruolo della cultura partecipativa e alle questioni di genere (e quindi politiche) che ora stanno emergendo in una discussione internazionale. Uno sport nato dalla letteratura e praticato da fan (almeno inizialmente, ora non più) si trova infatti ora a confrontarsi con problemi di ordine economico e di discriminazione proprio in virtù del successo che sta ottenendo.

Il fenomeno del disprezzo e della colpevolizzazione dei poveri emerge ormai diffusamente in canzoni, testi letterari, fumetti, forme testuali digitali della contemporaneità (ad esempio i meme), in Italia come nel resto del mondo. C'è chi risponde con ironia a questa ondata di hate speech, ma anche chi cerca di analizzare la questione inquadrandola in un discorso sociale e psicologico, per raccontare storie che illustrino una condizione sociale di isolamento, sostanzialmente schizoide, che non può che generare conflitti. Tra questi è Valerio Evangelisti, a cui è dedicato il focus dell'intervento.

L'articolo affronta la relazione non sempre facile, ma sempre sincera fra due dei principali intelettuali della "ilustración" spagnola: Meléndez Valdés y G. Melchor de Jovellanos.

Studio introduttivo alle principali problematiche legate alla trasmissione manoscritta di Lope de Vega, alla luce delle nuove prospettive metodologiche e delle recenti scoperte di documenti inediti, di cui viene data relazione con esempi specifici.