La biblioteca di Cicerone

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The RNA Binding Protein ESRP1 Fine-Tunes the Expression of Pluripotency-Related Factors in Mouse Embryonic Stem Cells

In pluripotent stem cells, there is increasing evidence for crosstalk between post-transcriptional and transcriptional networks, offering multifold steps at which pluripotency can be controlled. In addition to well-studied transcription factors, chromatin modifiers and miRNAs, RNA-binding proteins are emerging as fundamental players in pluripotency regulation. Here, we report a new role for the RNA-binding protein ESRP1 in the control of pluripotency. Knockdown of Esrp1 in mouse embryonic stem cells induces, other than the well-documented epithelial to mesenchymal-like state, also an increase in expression of the core transcription factors Oct4, Nanog and Sox2, thereby enhancing self-renewal of these cells. Esrp1-depleted embryonic stem cells displayed impaired early differentiation in vitro and formed larger teratomas in vivo when compared to control embryonic stem cells. We also show that ESRP1 binds to Oct4 and Sox2 mRNAs and decreases their polysomal loading. ESRP1 thus acts as a physiological regulator of the finely-tuned balance between self-renewal and commitment to a restricted developmental fate. Importantly, both mouse and human epithelial stem cells highly express ESRP1, pinpointing the importance of this RNA-binding protein in stem cell biology

Hyaluronic acid-decorated liposomes as innovative targeted delivery system for lung fibrotic cells

Collagen Tissue Disease-associated Interstitial Lung Fibrosis (CTD-ILDs) and Bronchiolitis Obliterans Syndrome (BOS) represent severe lung fibrogenic disorders, characterized by fibro-proliferation with uncontrolled extracellular matrix deposition. Hyaluronic acid (HA) plays a key role in fibrosis with its specific receptor, CD44, overexpressed by CTD-ILD and BOS cells. The aim is to use HA-liposomes to develop an inhalatory treatment for these diseases. Liposomes with HA of two molecular weights were prepared and characterized. Targeting efficiency was assessed toward CTD-ILD and BOS cells by flow cytometry and confocal microscopy and immune modulation by RT-PCR and ELISA techniques. HA-liposomes were internalized by CTD-ILD and BOS cells expressing CD44, and this effect increased with higher HA MW. In THP-1 cells, HA-liposomes decreased pro-inflammatory cytokines IL-1\u3b2, IL-12, and anti-fibrotic VEGF transcripts but increased TGF-\u3b2 mRNA. However, upon analyzing TGF-\u3b2 release from healthy donors-derived monocytes, we found liposomes did not alter the release of active pro-fibrotic cytokine. All liposomes induced mild activation of neutrophils regardless of the presence of HA. HA liposomes could be also applied for lung fibrotic diseases, being endowed with low pro-inflammatory activity, and results confirmed that higher MW HA are associated to an increased targeting efficiency for CD44 expressing LFs-derived from BOS and CTD-ILD patients

Persistent immune stimulation exacerbates genetically driven myeloproliferative disorders via stromal remodeling

Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated acute myelogenous leukemia (AML) patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy

Immune tuning scaffold for the local induction of a pro-regenerative environment

In mammals, tissue regeneration is accomplished through a well-regulated, complex cascade of events. The disruption of the cellular and molecular processes involved in tissue healing might lead to scar formation. Most tissue engineering approaches have tried to improve the regenerative outcome following an injury, through the combination of biocompatible materials, stem cells and bioactive factors. However, implanted materials can cause further healing impairments due to the persistent inflammatory stimuli that trigger the onset of chronic inflammation. Here, it is described at the molecular, cellular and tissue level, the body response to a functionalized biomimetic collagen scaffold. The grafting of chondroitin sulfate on the surface of the scaffold is able to induce a pro-regenerative environment at the site of a subcutaneous implant. The early in situ recruitment, and sustained local retention of anti-inflammatory macrophages significantly reduced the pro-inflammatory environment and triggered a different healing cascade, ultimately leading to collagen fibril re-organization, blood vessel formation, and scaffold integration with the surrounding native tissue

Effectiveness of Radiomic ZOT Features in the Automated Discrimination of Oncocytoma from Clear Cell Renal Cancer

Background: Benign renal tumors, such as renal oncocytoma (RO), can be erroneously diagnosed as malignant renal cell carcinomas (RCC), because of their similar imaging features. Computer-aided systems leveraging radiomic features can be used to better discriminate benign renal tumors from the malignant ones. The purpose of this work was to build a machine learning model to distinguish RO from clear cell RCC (ccRCC). Method: We collected CT images of 77 patients, with 30 cases of RO (39%) and 47 cases of ccRCC (61%). Radiomic features were extracted both from the tumor volumes identified by the clinicians and from the tumor’s zone of transition (ZOT). We used a genetic algorithm to perform feature selection, identifying the most descriptive set of features for the tumor classification. We built a decision tree classifier to distinguish between ROs and ccRCCs. We proposed two versions of the pipeline: in the first one, the feature selection was performed before the splitting of the data, while in the second one, the feature selection was performed after, i.e., on the training data only. We evaluated the efficiency of the two pipelines in cancer classification. Results: The ZOT features were found to be the most predictive by the genetic algorithm. The pipeline with the feature selection performed on the whole dataset obtained an average ROC AUC score of 0.87 ± 0.09. The second pipeline, in which the feature selection was performed on the training data only, obtained an average ROC AUC score of 0.62 ± 0.17. Conclusions: The obtained results confirm the efficiency of ZOT radiomic features in capturing the renal tumor characteristics. We showed that there is a significant difference in the performances of the two proposed pipelines, highlighting how some already published radiomic analyses could be too optimistic about the real generalization capabilities of the models

Inquinamento atmosferico e ricoveri ospedalieri urgenti in 25 citt? italiane: risultati del progetto EpiAir2 Air pollution and urgent hospital admissions in 25 Italian cities: results from the EpiAir2 project

OBJECTIVE: to evaluate the relationship between air pollution and hospital admissions in 25 Italian cities that took part in the EpiAir (Epidemiological surveillance of air pollution effects among Italian cities) project. DESIGN: study of time series with case-crossover methodology, with adjustment for meteorological and time-dependent variables. The association air pollution hospitalisation was analyzed in each of the 25 cities involved in the study; the overall estimates of effect were obtained subsequently by means of a meta-analysis. The pollutants considered were PM10, PM2.5 (in 13 cities only), NO2 and ozone (O3); this last pollutant restricted to the summer season (April-September). SETTING AND PARTICIPANTS: the study has analyzed 2,246,448 urgent hospital admissions for non-accidental diseases in 25 Italian cities during the period 2006- 2010; 10 out of 25 cities took part also in the first phase of the project (2001-2005). MAIN OUTCOME MEASURES: urgent hospital admissions for cardiac, cerebrovascular and respiratory diseases, for all age groups, were considered. The respiratory hospital admissions were analysed also for the 0-14-year subgroup. Percentage increases risk of hospitalization associated with increments of 10 μg/m3 and interquartile range (IQR) of the concentration of each pollutant were calculated. RESULTS: reported results were related to an increment of 10 μg/m3 of air pollutant. The percent increase for PM10 for cardiac causes was 0.34% at lag 0 (95%CI 0.04-0.63), for respiratory causes 0.75%at lag 0-5 (95%CI 0.25-1.25). For PM2.5, the percent increase for respiratory causes was 1.23% at lag 0- 5 (95%CI 0.58-1.88). For NO2, the percent increase for cardiac causes was 0.57%at lag 0 (95%CI 0.13-1.02); 1.29% at lag 0-5 (95%CI 0.52-2.06) for respiratory causes. Ozone (O3) did not turned out to be positively associated neither with cardiac nor with respiratory causes as noted in the previous period (2001-2005). CONCLUSION: the results of the study confirm an association between PM10, PM2.5, and NO2 on hospital admissions among 25 Italian cities. No positive associations for ozone was noted in this period.OBIETTIVO: valutare la relazione tra inquinamento atmosferico e ricoveri ospedalieri nelle citt? italiane partecipanti alla seconda fase del progetto EpiAir (Sorveglianza epidemiologica dell\u27inquinamento atmosferico: valutazione dei rischi e degli impatti nelle citt? italiane). DISEGNO: studio di serie temporali con metodologia case-crossover, con aggiustamento per i fattori temporali e meteorologici rilevanti. L\u27associazione inquinamento atmosferico- ospedalizzazioni ? stata analizzata in ciascuna delle 25 citt? in studio, le stime complessive di effetto sono state ottenute successivamente mediante una metanalisi. Gli inquinanti considerati sono stati il particolato (PM10), il biossido di azoto (NO2) e l\u27ozono (O3), quest\u27ultimo limitatamente al semestre estivo (da aprile a settembre). In 13 citt? in cui i dati erano disponibili ? stata analizzata anche la frazione fine del particolato (PM2.5). SETTING E PARTECIPANTI: lo studio ha esaminato 2.246.448 ricoveri ospedalieri urgenti per cause naturali di pazienti residenti e ricoverati, nel periodo 2006-2010, in 25 citt? italiane, di cui 10 gi? partecipanti alla prima fase del progetto EpiAir (2001-2005). PRINCIPALIMISURE DI OUTCOME: sono stati considerati i ricoveri ospedalieri urgenti per malattie cardiache, cerebrovascolari e respiratorie per tutte le fasce di et?. I ricoveri per cause respiratorie sono stati analizzati separatamente anche per la fascia di et? 0-14 anni. L\u27esposizione ? stata valutata per incremento sia di 10 μg/m3 sia pari all\u27intervallo interquartile (IQR) della concentrazione di ciascun inquinante. RISULTATI: considerando un incremento di 10 μg/m3 per inquinante, per il PM10 ? stato osservato un incremento percentuale di rischio per patologie cardiache dello 0,34%a lag 0 (IC95% 0,04-0,63), e per patologie respiratorie dello 0,75% a lag 0-5 (IC95% 0,25-1,25). Per il PM2.5 l\u27incremento percentuale di rischio per patologie respiratorie ? risultato dell\u271,23%a lag 0-5 (IC95%0,58-1,88). Per l\u27NO2 la stima di effetto per patologie cardiache ? risultata dello 0,57% a lag 0 (IC95% 0,13-1,02), e per patologie respiratorie dell\u271,29% a lag 0-5 (IC95% 0,52-2,06). L\u27ozono non ? risultato positivamente associato n? alle patologie cardiache n? a quelle respiratorie (a differenza del periodo 2001-2005). CONCLUSIONE: i risultati dello studio confermano l\u27effetto a breve termine dell\u27inquinamento atmosferico da PM10, PM2.5 e NO2 sulla morbosit?, in particolare respiratoria, nelle citt? italiane. Non sono state rilevate associazioni positive per l\u27O3

Importância do tratamento da Sífilis em gestantes: Importance of Syphilis treatment in pregnant women

Introdução: Dentre as infeções sexualmente transmissíveis a sífilis se destaca como grande problema de saúde pública. Apesar de ser uma doença de fácil manejo e evitável, se torna preponderante discutir a importância do tratamento das gestantes soropositivas, uma vez que há grandes sequelas, não só para a criança, como também reflexos nos coeficientes de saúde. Objetivos: Ratificar a importância do tratamento das gestantes com sífilis por meio da análise de dados epidemiológicos do SINAN. Métodos: Trata-se de um estudo ecológico compreendendo informações das unidades federativas do Brasil, a partir da observação, entre 2014-2019, da incidência e prevalência da sífilis em gestantes e da sífilis congênita e os coeficientes que rodeiam essa temática. Discussão: A sífilis durante a gestação ainda ocorre em proporções significativas nas mulheres, ratificada pelos 18,1% (24.130) dos conceptos menores de um ano de idade acometidos pela doença em 2019. Embora em 2019 o número de casos de gestantes com sífilis tenha se reduzido, percebe-se falha no esquema de tratamento sendo que apenas 2,3% (1.462) delas foram tratadas adequadamente. Apesar de 61.127 mulheres terem sido testadas para sífilis em 2019, apenas 32,9% (20.163) realizaram o pré-natal, o que evidencia falha na captação das gestantes para realização do mesmo. Conclusão: Fica evidente que tratar essas mulheres garante não só qualidade de vida para as gestantes bem como para as crianças, além de gerar melhores coeficientes que indicam melhor profilaxia, captação efetiva nas fases precoce, informação e efetivação das políticas públicas de saúde

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis