Inhibition of ERK1/2 signaling prevents bone marrow fibrosis by reducing osteopontin plasma levels in a myelofibrosis mouse model.

Clonal myeloproliferation and development of bone marrow (BM) fibrosis are the major pathogenetic events in myelofibrosis (MF). The identification of novel antifibrotic strategies is of utmost importance since the effectiveness of current therapies in reverting BM fibrosis is debated. We previously demonstrated that osteopontin (OPN) has a profibrotic role in MF by promoting mesenchymal stromal cells proliferation and collagen production. Moreover, increased plasma OPN correlated with higher BM fibrosis grade and inferior overall survival in MF patients. To understand whether OPN is a druggable target in MF, we assessed putative inhibitors of OPN expression in vitro and identified ERK1/2 as a major regulator of OPN production. Increased OPN plasma levels were associated with BM fibrosis development in the Romiplostim-induced MF mouse model. Moreover, ERK1/2 inhibition led to a remarkable reduction of OPN production and BM fibrosis in Romiplostim-treated mice. Strikingly, the antifibrotic effect of ERK1/2 inhibition can be mainly ascribed to the reduced OPN production since it could be recapitulated through the administration of anti-OPN neutralizing antibody. Our results demonstrate that OPN is a novel druggable target in MF and pave the way to antifibrotic therapies based on the inhibition of ERK1/2-driven OPN production or the neutralization of OPN activity.

Is black always the opposite of white? An investigation on the comprehension of antonyms in people with schizophrenia and in healthy participants.

The present investigation sought to expand our understanding of the cognitive processes underlying the recognition of antonyms and to evaluate whether these processes differed in patients with schizophrenia and in healthy controls. Antonymy is the most robust of the lexico-semantic relations and is relevant to both the mental organization of the lexicon and the organization of coherent discourse, as attested by the resurgence of interest in antonymy in the linguistic and psychological domains. In contrast, the vast literature on semantic processing in schizophrenia almost ignored antonymy. In this study, we tested the online comprehension of antonyms in 39 Italian patients with paranoid schizophrenia and in an equal number of pairwise-matched healthy controls. Participants read a definitional sentence fragment (e.g., the opposite of black is), followed by the correct antonym (white) or by a semantically unrelated word (nice), and judged whether or not the target word was correct. Patients were rather accurate in identifying antonyms, but compared to controls, they showed longer response times and higher priming scores, suggesting an exaggerated contextual facilitation. Presumably, this reflects a deficient controlled semantic processing and an overreliance on stored semantic representations.

Is the comprehension of idiomatic sentences indeed impaired in paranoid Schizophrenia? A window into semantic processing deficits.

Schizophrenia patients have been reported to be more impaired in comprehending non-literal than literal language since early studies on proverbs. Preference for literal rather than figurative interpretations continues to be documented. The main aim of this study was to establish whether patients are indeed able to use combinatorial semantic processing to comprehend literal sentences and both combinatorial analysis, and retrieval of pre-stored meanings to comprehend idiomatic sentences. The study employed a sentence continuation task in which subjects were asked to decide whether a target word was a sensible continuation of a previous sentence fragment to investigate idiomatic and literal sentence comprehension in patients with paranoid schizophrenia. Patients and healthy controls were faster in accepting sensible continuations than in rejecting non-sensible ones in both literal and idiomatic sentences. Patients were as accurate as controls in comprehending literal and idiomatic sentences, but they were overall slower than controls in all conditions. Once the contribution of cognitive covariates was partialled out, the response times (RTs) to sensible idiomatic continuations of patients did not significantly differ from those of controls. This suggests that the state of residual schizophrenia did not contribute to slower processing of sensible idioms above and beyond the cognitive deficits that are typically associated with schizophrenia.