Gli scrittori e la norma : interviste a Raffaello Baldini, Pierluigi Cappello, Luciano Cecchinel, Amedeo Giacomini e Ida Vallerugo

In queste interviste alcuni poeti italiani parlano del loro rapporto con la scrittura dialettale sottolineando il significato e l'importanza che hanno nella loro esperienza la scelta del dialetto, l'osservazione del linguaggio vivo, la continuità o la rottura nei confronti delle specifiche tradizioni dialettali e l'adozione e/o la ricerca di una norma scritta.In these interviews, a number of Italian poets speak of their relation with dialect writings, underlining the significance and importance, within their experience, of the choice of dialect, observations of living language, continuity or breakdown in relation to specific dialect traditions and the adoption and/or search for a written standard

Purification and Characterization of Adipose-Derived Stem Cells From Patients With Lipoaspirate Transplant

Techniques for medical tissue regeneration require an abundant source of human adult stem cells. There is increasing evidence that adipose stem cells contribute to restoration of tissue vascularization and organ function. The object of our study was to isolate and characterize adult adipose-derived stem cells from patients undergoing on lipoaspirate transplant with the aim to improve tissue regeneration. Adipose-derived stem cells were isolated and purified from the lipoaspirate of 15 patients and characterized for CD markers and the ability to differentiate toward the adipogenic lineage. We found that purified adipose stem cells express high level of CD49d, CD44, CD90, CD105, CD13, and CD71 and these markers of staminality were maintained at high level for at least 3 months and seven passages of in vitro culture. As expected, these cells resulted negative for the endothelial and hematopoietic-specific markers CD31, CD106, CD34, and CD45. Differentiation towards adipogenic lineage demonstrated that purified adipose-derived stem cells are still able to become adipocytes at least 3 months after in vitro culture. The analysis of Akt and MAPK phosphorylation confirmed a modulation of their activity during differentiation. Interestingly, we established for the first time that, among the p53 family members, a strong upregulation of p63 expression occurs in adipocytic differentiation, indicating a role for this transcription factor in adipocytic differentiation. Taken together, these data indicate that purified lipoaspirate-derived stem cells maintain their characteristic of staminality for a long period of in vitro culture, suggesting that they could be applied for cell-based therapy to improve autologous lipoaspirate transplant

Induction of ErbB-3 Expression by α6β4 Integrin Contributes to Tamoxifen Resistance in ERβ1-Negative Breast Carcinomas

Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear or membrane ER and growth factor receptor pathways may be involved in endocrine resistance. We recently found a functional interaction between alpha6beta4 integrin and ErbB-3 receptor to maintain the PI3K/Akt survival pathway of mammary tumour cells. We sought to improve understanding of this process in order to provide the involvement of both receptors insight into mechanism of Tamoxifen resistance.Using human breast cancer cell lines displaying different levels of alpha6beta4 and ErbB-3 receptors and a series of 232 breast cancer biopsies from patients submitted to adjuvant Tamoxifen monotherapy for five years, we evaluated the functional interaction between both receptors in relationship to Tamoxifen responsiveness. In mammary carcinoma cells, we evidenced that the alpha6beta4 integrin strongly influence Akt phosphorylation through ErbB-3 protein regulation. Moreover, the ErbB-3 inactivation inhibits Akt phosphorylation, induces apoptosis and inhibits in vitro invasion favouring Tamoxifen responsiveness. The analysis of human tumors revealed a significant relationship between alpha6beta4 and ErbB-3 in P-Akt-positive and ERbeta1-negative breast cancers derived from patients with lower disease free survival.We provided evidence that a strong relationship occurs between alpha6beta4 and ErbB-3 positivity in ERbeta1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERbeta1-negative breast cancer derived from patients with lower DFS indicating that both receptors are clinically relevant in predicting the response to Tamoxifen

SEMA6A/RhoA/YAP axis mediates tumor-stroma interactions and prevents response to dual BRAF/MEK inhibition in BRAF-mutant melanoma

Background: Despite the promise of dual BRAF/MEK inhibition as a therapy for BRAF-mutant (BRAF-mut) melanoma, heterogeneous responses have been observed in patients, thus predictors of benefit from therapy are needed. We have previously identified semaphorin 6A (SEMA6A) as a BRAF-mut-associated protein involved in actin cytoskeleton remodeling. The purpose of the present study is to dissect the role of SEMA6A in the biology of BRAF-mut melanoma, and to explore its predictive potential towards dual BRAF/MEK inhibition. Methods: SEMA6A expression was assessed by immunohistochemistry in melanoma cohort RECI1 (N = 112) and its prognostic potential was investigated in BRAF-mut melanoma patients from DFCI and TCGA datasets (N = 258). The molecular mechanisms regulated by SEMA6A to sustain tumor aggressiveness and targeted therapy resistance were investigated in vitro by using BRAF-mut and BRAF-wt melanoma cell lines, an inducible SEMA6A silencing cell model and a microenvironment-mimicking fibroblasts-coculturing model. Finally, SEMA6A prediction of benefit from dual BRAF/MEK inhibition was investigated in melanoma cohort RECI2 (N = 14). Results: Our results indicate higher protein expression of SEMA6A in BRAF-mut compared with BRAF-wt melanoma patients and show that SEMA6A is a prognostic indicator in BRAF-mut melanoma from TCGA and DFCI patients cohorts. In BRAF-mut melanoma cells, SEMA6A coordinates actin cytoskeleton remodeling by the RhoA-dependent activation of YAP and dual BRAF/MEK inhibition by dabrafenib+trametinib induces SEMA6A/RhoA/YAP axis. In microenvironment-mimicking co-culture condition, fibroblasts confer to melanoma cells a proliferative stimulus and protect them from targeted therapies, whereas SEMA6A depletion rescues the efficacy of dual BRAF/MEK inhibition. Finally, in BRAF-mut melanoma patients treated with dabrafenib+trametinib, high SEMA6A predicts shorter recurrence-free interval. Conclusions: Overall, our results indicate that SEMA6A contributes to microenvironment-coordinated evasion of melanoma cells from dual BRAF/MEK inhibition and it might be a good candidate predictor of short-term benefit from dual BRAF/MEK inhibition

Compreensão das características fisiopatológicas da hipertensão arterial sistêmica em relação a senescência: uma revisão de literatura

Introdução: A Hipertensão Arterial Sistêmica (HAS) é uma doença prevalente nos diversos âmbitos sociais e devido ao processo de envelhecimento natural do organismo, os idosos são mais propensos a adquirir essa doença. Objetivo: compreender as principais características relatadas na Hipertensão Arterial Sistêmica em associação ao processo fisiológico de envelhecimento, evidenciando, portanto, a importância do controle de fatores de risco evitáveis. Metodologia: Trata-se de uma revisão integrativa da literatura, por proporcionar uma síntese dos resultados obtidos através de pesquisas publicadas. Para direcionar a pesquisa, adotou-se como pergunta norteadora: “Quais as principais características associadas entre a Hipertensão Arterial Sistêmica e a senescência?" Para construção da pesquisa, a coleta e análise de dados foi realizada através do Portal da Biblioteca Virtual da Saúde e das bases de dados Medical Literature Analysis and Retrievel System Online via PubMed e Google Acadêmico através dos seguintes Descritores em Ciências da Saúde (DeCS): “Hipertensão Arterial Sistêmica”, “Senescência” e “Sintomas locais” combinados entre si pelo operador booleano AND com seus respectivos correspondentes no Mesh Terms. Discussão: Segundo dados das Pesquisa Nacional de Saúde (PNS) de 2013, aproximadamente 22% da população considerava-se portador de HA, sendo que indivíduos em uso de medicamentos anti-hipertensivos e com pressão arterial ≥ 140 por 90 mmHg superou a média de 33%. Por certo, pacientes mais idosos contam com uma maior rigidez arterial, atuando como a principal condição predisponente para elevação da pressão arterial. Conclusão: Com o aumento da expectativa de vida, há a prevalência e incidência maior de doenças progressivas, como a hipertensão arterial. Com isso, é essencial conduzir o devido conhecimento sobre os fatores de risco da HAS para a população, em especial os idosos, a fim de destacar a importância da prevenção e estimular o tratamento da pessoa idosa com Hipertensão Arterial Sistêmica

A Land-Use Perspective for Birdstrike Risk Assessment: The Attraction Risk Index

Collisions between aircraft and birds, birdstrikes, pose a serious threat to aviation safety. The occurrence of these events is influenced by land-uses in the surroundings of airports. Airports located in the same region might have different trends for birdstrike risk, due to differences in the surrounding habitats. Here we developed a quantitative tool that assesses the risk of birdstrike based on the habitats within a 13-km buffer from the airport. For this purpose, we developed Generalized Linear Models (GLMs) with binomial distribution to estimate the contribution of habitats to wildlife use of the study area, depending on season. These GLMs predictions were combined to the flight altitude of birds within the 13-km buffer, the airport traffic pattern and the severity indices associated with impacts. Our approach was developed at Venice Marco Polo International airport (VCE), located in northeast Italy and then tested at Treviso Antonio Canova International airport (TSF), which is 20 km inland. Results from the two airports revealed that both the surrounding habitats and the season had a significant influence to the pattern of risk. With regard to VCE, agricultural fields, wetlands and urban areas contributed most to the presence of birds in the study area. Furthermore, the key role of distance of land-uses from the airport on the probability of presence of birds was highlighted. The reliability of developed risk index was demonstrated since at VCE it was significantly correlated with bird strike rate. This study emphasizes the importance of the territory near airports and the wildlife use of its habitats, as factors in need of consideration for birdstrike risk assessment procedures. Information on the contribution of habitats in attracting birds, depending on season, can be used by airport managers and local authorities to plan specific interventions in the study area in order to lower the risk.Collisions between aircraft and birds, birdstrikes, pose a serious threat to aviation safety. The occurrence of these events is influenced by land-uses in the surroundings of airports. Airports located in the same region might have different trends for birdstrike risk, due to differences in the surrounding habitats. Here we developed a quantitative tool that assesses the risk of birdstrike based on the habitats within a 13-km buffer from the airport. For this purpose, we developed Generalized Linear Models (GLMs) with binomial distribution to estimate the contribution of habitats to wildlife use of the study area, depending on season. These GLMs predictions were combined to the flight altitude of birds within the 13-km buffer, the airport traffic pattern and the severity indices associated with impacts. Our approach was developed at Venice Marco Polo International airport (VCE), located in northeast Italy and then tested at Treviso Antonio Canova International airport (TSF), which is 20 km inland. Results from the two airports revealed that both the surrounding habitats and the season had a significant influence to the pattern of risk. With regard to VCE, agricultural fields, wetlands and urban areas contributed most to the presence of birds in the study area. Furthermore, the key role of distance of land-uses from the airport on the probability of presence of birds was highlighted. The reliability of developed risk index was demonstrated since at VCE it was significantly correlated with bird strike rate. This study emphasizes the importance of the territory near airports and the wildlife use of its habitats, as factors in need of consideration for birdstrike risk assessment procedures. Information on the contribution of habitats in attracting birds, depending on season, can be used by airport managers and local authorities to plan specific interventions in the study area in order to lower the risk

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery