Lung Cancer Organoids. The Rough Path to Personalized Medicine

Lung cancer is the leading cause of cancer death worldwide. Despite significant advances in research and therapy, a dismal 5-year survival rate of only 10–20% urges the development of reliable preclinical models and effective therapeutic tools. Lung cancer is characterized by a high degree of heterogeneity in its histology, a genomic landscape, and response to therapies that has been traditionally difficult to reproduce in preclinical models. However, the advent of three-dimensional culture technologies has opened new perspectives to recapitulate in vitro individualized tumor features and to anticipate treatment efficacy. The generation of lung cancer organoids (LCOs) has encountered greater challenges as compared to organoids derived from other tumors. In the last two years, many efforts have been dedicated to optimizing LCO-based platforms, resulting in improved rates of LCO production, purity, culture timing, and long-term expansion. However, due to the complexity of lung cancer, further advances are required in order to meet clinical needs. Here, we discuss the evolution of LCO technology and the use of LCOs in basic and translational lung cancer research. Although the field of LCOs is still in its infancy, its prospective development will likely lead to new strategies for drug testing and biomarker identification, thus allowing a more personalised therapeutic approach for lung cancer patients

The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms

: The mitogen-activated protein kinase (MAPK) and PI3K pathways are regulated by extensive crosstalk, occurring at different levels. In tumors, transactivation of the alternate pathway is a frequent "escape" mechanism, suggesting that combined inhibition of both pathways may achieve synergistic antitumor activity. Here we show that, in the M14 melanoma model, simultaneous inhibition of both MEK and mammalian target of rapamycin (mTOR) achieves synergistic effects at suboptimal concentrations, but becomes frankly antagonistic in the presence of relatively high concentrations of MEK inhibitors. This observation led to the identification of a novel crosstalk mechanism, by which either pharmacologic or genetic inhibition of constitutive MEK signaling restores phosphatase and tensin homolog (PTEN) expression, both in vitro and in vivo, and inhibits downstream signaling through AKT and mTOR, thus bypassing the need for double pathway blockade. This appears to be a general regulatory mechanism and is mediated by multiple mechanisms, such as MAPK-dependent c-Jun and miR-25 regulation. Finally, PTEN upregulation appears to be a major effector of MEK inhibitors' antitumor activity, as cancer cells in which PTEN is inactivated are consistently more resistant to the growth inhibitory and anti-angiogenic effects of MEK blockade

New Landscapes and Horizons in Hepatocellular Carcinoma Therapy

Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient

Anna Göldin. Letzte Hexe. di Eveline Hasler. Proposta di traduzione di alcuni estratti

L’obiettivo del presente elaborato è quello di fornire una proposta di traduzione letteraria dal tedesco all’italiano. Il lavoro è stato svolto sul romanzo storico-biografico Anna Göldin. Letzte Hexe., incentrato sulla figura di una domestica svizzera decapitata con l’accusa di stregoneria nel 1782. Si è scelto di tradurre l’incipit per dare subito un’idea dello stile dell’autrice e del suo approccio al tema trattato e un passaggio particolarmente ricco di pathos, in cui la donna in fuga dalla giustizia rievoca i dolorosi momenti del processo per infanticidio, crimine del quale fu accusata in seguito alla morte del figlio appena nato. L’elaborato è strutturato nel seguente ordine: dopo una breve introduzione sull’autrice e sul romanzo si spiegherà che cosa s’intende per traduzione letteraria, per passare poi alla proposta di traduzione, accompagnata dal testo originale a fronte e concludere con un commento relativo alle strategie traduttive e alle difficoltà riscontrate in corso d’opera

Il discorso politico sulla migrazione in Germania e Austria: analisi parziale assistita da corpora della rete semantico-lessicale di alcuni termini chiave.

Il presente elaborato si propone di indagare il discorso politico relativo al fenomeno migratorio in due paesi europei, la Germania e l’Austria, mediante un’analisi parziale della rete semantico-lessicale di alcuni termini chiave. Entrambi i paesi, infatti, hanno avuto un ruolo di spicco nel dibattito europeo sulla migrazione e nella gestione in prima linea del fenomeno migratorio. A tal fine è parso ragionevole e pregnante restringere il campo d'analisi agli anni 2014-2019 e circoscrivere l’ambito della ricerca alle sedute plenarie dei parlamenti dei due paesi, il Bundestag per la Germania e il Nationalrat per l’Austria. I discorsi estrapolati dai resoconti stenografici delle sedute sono confluiti in due corpora specialistici: MI-AT, per l'Austria e MI-DE, per la Germania. In un primo momento, abbiamo indagato l’uso delle unità lessicali da parte delle forze politiche dei due paesi nei due corpora specialistici; in seguito, abbiamo ripetuto l’analisi delle stesse unità lessicali nel web corpus deTenTen13, in ottica contrastiva. Il lavoro è suddiviso in due parti: una prima parte dedicata all’impianto teorico ed una seconda parte incentrata sull’analisi. Nel primo capitolo passeremo brevemente in rassegna alcune caratteristiche della lingua politica e chiariremo il ruolo della metafora e dei frame nella strutturazione dell’esperienza e il loro contributo all’interpretazione della realtà da una determinata prospettiva. Nel secondo capitolo descriveremo i concetti di corpus e discorso e offriremo una panoramica della linguistica dei corpora e dei CADS (Corpus Assisted Discourse Studies). Nel terzo capitolo daremo conto dei criteri osservati in fase di raccolta dei dati e dell’approccio metodologico adottato. Il quarto capitolo sarà dedicato all’analisi delle singole unità lessicali nei due corpora ad hoc MI-AT e MI-DE e nel web corpus deTenTen13. Infine, riassumeremo quanto emerso dall’analisi suggerendo alcuni spunti per eventuali approfondimenti futuri

Chronic and acute alcohol exposure prevents monocyte-derived dendritic cells from differentiating and maturing

Increasing evidence suggests that alcohol abuse may be linked to adverse immunomodulatory effects on immune responses. Our study was undertaken to clarify the immunological consequences of chronic and acute alcohol exposure on differentiation and maturation of human dendritic cells (DCs). Using immunochemical and cytofluorimetric analysis we determined the phenotype and functions of monocyte-derived DCs from alcoholics and healthy subjects and analyzed their ability to respond to lipopolysaccharide (LPS) in the presence or absence of ethanol (EtOH) exposure. Our results showed that alcoholics' monocytes differentiated to immature DCs with altered phenotype and functions (alciDCs). Alc-iDCs showed fewer CD1a+ cells, weaker CD86 expression and higher HLA-DR expression associated with lower endocytosis and allostimulatory functions than iDCs from healthy subjects (control-iDCs). Despite these impairments, alc-iDCs produced TNF-α and IL-6 in large amounts. LPS stimulation failed to induce full phenotypical and functional alc-iDC maturation. In vitro acute EtOH exposure also prevented alc-iDCs and control-iDCs from maturing in response to LPS. T-cell priming experiments showed that EtOH treatment prevented LPS-stimulated control-iDCs from priming and polarizing naïve allogeneic T cells into Th1 cells, thus favouring a predominant Th2 environment. Collectively, our results provide evidence that chronic and acute alcohol exposure prevents DCs from differentiating and maturing in response to a microbial stimulus. Copyright © by BIOLIFE, s.a.s