BID and the α-bisabolol-triggered cell death program: converging on mitochondria and lysosomes

\u3b1-Bisabolol (BSB) is a plant-derived sesquiterpene alcohol able to trigger regulated cell death in transformed cells, while deprived of the general toxicity in several mouse models. Here, we investigated the involvement of lysosomal and mitochondrial compartments in the cytotoxic effects of BSB, with a specific focus on the BH3-only activator protein BID. We found that BSB particularly accumulated in cancer cell lines, displaying a higher amount of lipid rafts as compared to normal blood cells. By means of western blotting and microscopy techniques, we documented rapid BSB-induced BID translocation to lysosomes and mitochondria, both of them becoming dysfunctional. Lysosomal membranes were permeabilized, thus blocking the cytoprotective autophagic flux and provoking cathepsin B leakage into the cytosol. Multiple flow cytometry-based experiments demonstrated the loss of mitochondrial membrane potential due to pore formation across the lipid bilayer. These parallel events converged on neoplastic cell death, an outcome significantly prevented by BID knockdown. Therefore, BSB promoted BID redistribution to the cell death executioner organelles, which in turn activated anti-autophagic and proapoptotic mechanisms. This is an example of how xenohormesis can be exploited to modulate basic cellular programs in cancer

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a-/- mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, \u3b3-synuclein and phospho-tau proteins in Vps13a-/- basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a-/- Lyn-/- showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a-/- hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients

Città o evento? Rappresentare e costruire la città attraverso i Festival e i grandi eventi

The cities are becoming more and more events, space for cultural events, major exhibitions, International sporting events, political conventions. An emblematic case is represented by the proliferation of cultural festivals in cities and territories of all sizes. What is relationship between these events and the city? Far from being simple headquarters and exhibition places of cultural venues, cities become active participants of the event organized to coincide with it. What effect produce these forms of hybridization between city and cultural event? How does the city make sense? And how does it contribute in "Making the city"? Through a specific case study, this essay will reflect on how the event organization constitutes a new form of representation of the city and the territory, as well as a new form of city, concentrating in itself material and immaterial, morphology and discourse, system and process

YAP1 acts as oncogenic target of 11q22 amplification in multiple cancer subtypes

The transcriptional coactivator YAP1 is a critical effector of the human Salvador-Warts-Hippo pathway. Literature data report apparently discrepant results on the carcinogenic role of YAP1, which acts either as oncogene or as tumor suppressor in different in vitro and in vivo models. Furthermore, genomic amplification events of 11q22 locus encompassing YAP1 gene have been detected in multiple tumor types but there is limited direct evidence about the oncogenic role of endogenous YAP1 within in the amplicon. We screened a panel of human tumor samples and cancer cell lines and identified that the YAP1 amplification event is actually present in up to 23% of the cases. We exploited EKVX (lung cancer), CaSki (cervical cancer) and RO82 (thyroid cancer) cell lines harboring both genomic YAP1 amplification and YAP1 protein overexpression, in order to study the effects of downregulation of endogenous YAP1 by RNA-interference strategies. Class comparison analysis of gene expression profiling data identified 707 statistically significantly modulated genes (multivariable global test p-value = 0.002) that were functionally annotated for cell proliferation and cellular movement ontologies. Mechanistic studies of the identified perturbed pathways revealed that YAP1 silencing significantly decreased cell proliferation and cell cycle perturbation associated with upregulation of p21 and p27 cell-cycle inhibitors, reduced cell migration (p<0.048) and anchorage-independent growth (p<0.02). In CaSki cell line, YAP1 silencing induced significantly increased sensitivity and cell-death response to cisplatin treatment (p=0.011) as well as reduction of in-vivo tumorigenic potential (p=0.027). Overall, these results establish that YAP1 is a direct oncogenic target of the 11q22 amplicon in previously unreported cancer types and support the relevance of such genetic aberration in carcinogenesis in a fraction of multiple tumor types

Quadruple-negative GIST is a sentinel for unrecognized Neurofibromatosis Type 1 syndrome

The majority of Gastrointestinal Stromal Tumors (GISTs) are driven by KIT, PDGFRA or, less commonly, BRAF mutations, and SDH gene inactivation is involved in a limited fraction of gastric lesions. However, about 10% of GISTs are devoid of any of such alterations and are poorly responsive to standard treatments. This study aims to shed light on the molecular drivers of quadruple-negative GISTs

SHARK-NIR, first results of the commissioning at LBT

International audienceSHARK-NIR, first results of the commissioning at LB

SHARK-NIR, first results of the commissioning at LBT

SHARK-NIR is an instrument which provides direct imaging, both coronagraphic and non-coronagraphic and with the possibility to perform dual-band imaging and low-resolution spectroscopy in Y, J and H bands, with the main scientific goal of detecting exoplanets, and characterizing already known planets, young stellar systems, jets and disks. SHARK-NIR takes advantage of the excellent performance of the Large Binocular Telescope AO systems, the wavefront sensors of which have been recently upgraded to SOUL. The latter is delivering a very good performance also at faint magnitude, opening to science otherwise difficult to be achieved, as for example AGN and QSO morphological studies. To fully exploit the just mentioned science cases, binocular observations will be performed using SHARK-NIR in combination with SHARK-VIS (operating in B, V, R and I bands) and LMIRCam of LBTI (operating from K to M bands), in a way to exploit coronagraphic observations in three different wavelengths. The instrument has passed the preliminary acceptance Europe in March 2022, being shipped immediately after at LBT, and re-integrated, installed and characterized daytime in three pre-commissioning run at the telescoped. SHARK-NIR had a very successful first light in January this year, and we will report of the results obtained in the three commissioning runs performed in the first half of 2023

SHARK-NIR, first results of the commissioning at LBT

International audienceSHARK-NIR, first results of the commissioning at LB