SPARC, a matricellular protein that protects cancer from therapy

The matricellular protein SPARC (secreted protein acidic and rich in cysteine) is a master regulator of tissue stroma; it is expressed during tissue remodeling and repair and its impaired regulation has a role in fibrotic responses, in determining the composition of the tumor-associated stroma and, less expected, in regulating the immune response. The complexity of studying SPARC in cancer stems from its concomitant or alternative expression in tumor and/or stroma cells depending on the tumor histotypes. Extracellular matrix (ECM) gene profile of human breast carcinomas correlates SPARC expression with prognosis and response to therapy. In particular, a subgroup of breast tumors can be identified based on ECM gene signature headed by SPARC that correlates with tumor grade, bad prognosis and poor response to therapy. Epithelial to mesenchymal transition (EMT) has been associated to drug resistance and SPARC has been implicated in EMT. Nevertheless the source of SPARC and its path toward EMT and the associated drug resistance have not been identified yet. I have used a well-defined model of transgenic mouse mammary carcinoma expressing the mutated rat oncogene c-erB2 (HER-2/neu), under the mouse mammary turn or virus promoter, backcrossed with Sparc-/- mice to establish mammary carcinoma cell lines devoid of SPARC expression, in which SPARC can be restored by retroviral gene transduction. With this isogenic cell lines I have been able to show that SPARC expression in tumor cells induces EMT only in vivo, indicating that EMT is a micro environmental and not a cell autonomous process. Moreover, SPARC expressing tumors became resistant to treatment with Doxil (Doxil, a pegylated form of Doxorubicin). Investigating the environmental players responsible of EMT in SPARC transduced tumors, I found that myeloid cells and particularly the so called myeloid derived suppressor cells (MDSC) have a role in EMT and drug resistance depending on SPARC. SPARC does not change the number or ratio between the Ly6Ghigh and the Ly6Glow fractions of CD11b MDSC rather it determines the immunosuppressive phenotype of recruited myeloid cells. The data show that SPARC-forced expression increased the activation of pro-turn oral (CCL2, CCL5) and immunosuppressive (ArgI, NOS2, Cox-2) genes in monocyte-MDSC (the Ly6Glow fraction). Furthermore, the role of myeloid cells recruited in Doxil resistance and EMT has been proven adding bisphosphonate to Doxil during treatment. , Bisphosphonates have been shown to inhibit induction and function of myeloid suppressor cells. Indeed, Bisphosphonates addition reverted EMT, the immunosuppressive phenotype of myeloid cells and rendered SPARC-producing tumors sensitive to Doxil administration

Uno studio sui delitti di turbativa. La tutela della concorrenza tra tipicità e proporzionalità dell'intervento penale

I delitti di turbativa sono stati di recente oggetto di un rinnovato interesse da parte del diritto vivente, acquisendo un ruolo centrale in relazione allo statuto penale della pubblica amministrazione. L’indirizzo estensivo condiviso da gran parte della giurisprudenza ha, infatti, trovato ulteriori sviluppi, che rasentano l’analogia in malam partem se non un vero e proprio “creazionismo ermeneutico”. Tali profili di tensione con le garanzie fondamentali della sfera penale sono da declinare in una prospettiva – almeno in parte – nuova, in ragione delle significative riforme che hanno investito negli ultimi mesi la regolamentazione dei contratti pubblici a livello europeo e nazionale. La posta in gioco è alta, atteso il rischio di vanificare sul piano sanzionatorio gli sforzi intrapresi per adeguare la disciplina interna agli standard di tutela sovranazionali. Lo studio si propone, allora, di rileggere i delitti di turbativa secondo le direttrici offerte dal principio di tipicità, selezionando i casi paradigmatici in base alla tassatività delle diverse sottofattispecie. Preso atto delle incongruenze semantiche e della debolezza dei contrassegni di tipicità, si prospetta un approccio ermeneutico di segno restrittivo ancorato al perimetro testuale delle norme incriminatrici. In seconda battuta, l’indagine si spinge a verificare la legittimità delle scelte di tutela compiute dal legislatore rispetto alla ragionevolezza delle incriminazioni: il giudizio di proporzionalità è calato nella dimensione punitiva, allo scopo di razionalizzare il novero dei delitti di turbativa e contrastare il “doppio” chilling effect che ostacola l’attività degli operatori economici e dei funzionari pubblici

Could gestational diabetes mellitus be managed through dietary bioactive compounds? Current knowledge and future perspectives

Gestational diabetes mellitus (GDM) is a serious problem growing worldwide that needs to be addressed with urgency in consideration of the resulting severe complications for both mother and fetus. Growing evidence indicates that a healthy diet rich in fruit, vegetables, nuts, extra-virgin olive oil and fish has beneficial effects in both the prevention and management of several human diseases and metabolic disorders. In this review, we discuss the latest data concerning the effects of dietary bioactive compounds such as polyphenols and PUFA on the molecular mechanisms regulating glucose homoeostasis. Several studies, mostly based on in vitro and animal models, indicate that dietary polyphenols, mainly flavonoids, positively modulate the insulin signalling pathway by attenuating hyperglycaemia and insulin resistance, reducing inflammatory adipokines, and modifying microRNA (miRNA) profiles. Very few data about the influence of dietary exposure on GDM outcomes are available, although this approach deserves careful consideration. Further investigation, which includes exploring the 'omics' world, is needed to better understand the complex interaction between dietary compounds and GDM

An epistatic mini-circuitry between the transcription factors Snail and HNF4a controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

Preservation of the epithelial state involves the stable repression of EMT program while maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular mini-circuitry between master elements of these biological processes, may provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4, directly represses the expression of the epithelial microRNAs-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4, previously identified as a transcriptional repressor of Snail, induces the microRNAs-34a and -200a, b, c that, when silenced, causes epithelial dedifferentiation and reacquisition of stem traits. Altogether these data unveiled Snail, HNF4 and microRNAs -200a, b, c and -34a as epistatic elements controlling hepatic stem cell maintenance/differentiation

Curcumin: could this compound be useful in pregnancy and pregnancy-related complications?

Curcumin, the main polyphenol contained in turmeric root (Curcuma longa), has played a significant role in medicine for centuries. The growing interest in plant-derived substances has led to increased consumption of them also in pregnancy. The pleiotropic and multi-targeting actions of curcumin have made it very attractive as a health-promoting compound. In spite of the beneficial effects observed in various chronic diseases in humans, limited and fragmentary information is currently available about curcumin's effects on pregnancy and pregnancy-related complications. It is known that immune-metabolic alterations occurring during pregnancy have consequences on both maternal and fetal tissues, leading to short- and long-term complications. The reported anti-inflammatory, antioxidant, antitoxicant, neuroprotective, immunomodulatory, antiapoptotic, antiangiogenic, anti-hypertensive, and antidiabetic properties of curcumin appear to be encouraging, not only for the management of pregnancy-related disorders, including gestational diabetes mellitus (GDM), preeclampsia (PE), depression, preterm birth, and fetal growth disorders but also to contrast damage induced by natural and chemical toxic agents. The current review summarizes the latest data, mostly obtained from animal models and in vitro studies, on the impact of curcumin on the molecular mechanisms involved in pregnancy pathophysiology, with the aim to shed light on the possible beneficial and/or adverse effects of curcumin on pregnancy outcomes

Bacterial-cellulose-derived carbonaceous electrode materials for water desalination via capacitive method: The crucial role of defect sites

Electrosorptive desalination is a very simple and appealing approach to satisfy the increasing demand for drinking water. The large-scale application of this technology calls for the development of easy-to-produce, cheap and highly performing electrode materials and for the identification and tailoring of their most influential properties, as well. Here, biosynthesised bacterial cellulose is used as a carbon precursor for the production of three-dimensional nanostructures endowed with hierarchically porous architecture and different density and type of intrinsic and hetero-atom induced lattice defects. The produced materials exhibit unprecedented desalination capacities for carbon-based electrodes. At an initial concentration of 585 mg L−1 (10 mmol L−1), they are able to remove from 55 to 79 mg g−1 of salt; as the initial concentration rises to 11.7 g L−1 (200 mmol L−1), their salt adsorption capacity reaches values ranging between 1.03 and 1.35 g g−1. The results of the thorough material characterisation by complementary techniques evidence that the relative amount of oxygenated surface functional species enhancing the electrode wettability play a crucial role at lower NaCl concentrations, whereas the availability of active non-sp2 defect sites for adsorption is mainly influential at higher salt concentrations.L.U., M.A.C. and A.E. gratefully thank GIU18/216 - UPV/EHU Research Group for the financial support to their work

Serum Exosomal microRNA-21, 222 and 124-3p as Noninvasive Predictive Biomarkers in Newly Diagnosed High-Grade Gliomas: A Prospective Study

Background: High-grade gliomas (HGG) are malignant brain tumors associated with frequent recurrent disease. Clinical management of HGG patients is currently devoid of blood biomarkers for early diagnosis, monitoring therapeutic effects and predicting recurrence. Different circulating miRNAs, both free and associated with exosomes, are described in patients with HGG. We previously identified miR-21, miR-222 and miR-124-3p purified from serum exosomes as molecular signature to help pre-operative clinical diagnosis and grading of gliomas. The aim of the present study was to verify this signature as a tool to assess the effect of treatment and for the early identification of progression in newly diagnosed HGG patients. Material and Methods: Major inclusion criteria were newly diagnosed, histologically confirmed HGG patients, no prior chemotherapy, ECOG PS 0-2 and patients scheduled for radiochemotherapy with temozolomide as first-line treatment after surgery. RANO criteria were used for response assessment. Serum was collected at baseline and subsequently at each neuroradiological assessment. mir-21, -222 and -124-3p expression in serum exosomes was measured in all samples. Results: A total number of 57 patients were enrolled; 41 were male, 52 with glioblastoma and 5 with anaplastic astrocytoma; 18 received radical surgery. HGG patients with higher exosomal miRNA expression displayed a statistically significant lower progression-free survival and overall survival. Increased expression of miR-21, -222 and -124-3p during post-operative follow-up was associated with HGG progression. Conclusions: These data indicate that miR-21, -222 and -124-3p in serum exosomes may be useful molecular biomarkers for complementing clinical evaluation of early tumor progression during post-surgical therapy in patients with HGG

Balancing the trade-off between learning prospects and spillover risks: MNC subsidiaries' vertical linkage patterns in developed countries

This paper investigates local vertical linkages of foreign subsidiaries and the dual role of such linkages as conduits for learning as well as potential channels for spillovers to competitors. On the basis of data from 97 subsidiaries, we analyze the quality of such linkages under varying levels of competition and subsidiary capabilities. Our theoretical development and the results from the analysis document a far more complex and dynamic relationship between levels of competition and MNCs’ local participation in knowledge intensive activities, i.e. learning and spillovers, than previous studies do. We find a curvilinear relationship between the extent of competitive pressure and the quality of local linkages confirming our argument of a trade-off between learning prospects and spillover risks. Furthermore, the level of subsidiary capabilities moderates this relationship

Knowledge, attitudes and practices towards COVID-19 among nursing students of the University of Palermo: results from an online survey

Introduction: The aim of the study was to evaluate the knowledge, attitude and practices towards SARS-CoV-2 among nursing students of University of Palermo during the rapid rise period of the COVID-19 pandemic. Materials and methods: This is cross-sectional study. A survey was provided to all nursing students and consisted of two parts: demographics and Knowledge, Attitude and Practices (KAP) survey. A multivariate linear regression model was used and adjusted Odds Ratios (aOR) are presented. Results: 575 students were interviewed, and their mean age was 22.29 ± 4.2. The overall score indicates good knowledge (p=0.046) and good practices among the four courses of study (p=0.038). Multivariate linear regression showed that Attitude score (b = -0.29; p = 0.024) and Knowledge score (b = 0.10; p = 0.026) adjusted for age, gender, year of study, perceived economic status, perceived health status were significantly associated with Practice score. Conclusion: Our results suggest that proper health education is useful for encouraging optimistic attitudes and maintaining safe practices among future category of nurses

The Italian Implementation of the EU Directives on Procedural Safeguards for Accused Persons in Criminal Proceedings

Questo saggio è stato sviluppato nel corso di un progetto di ricerca di 30 mesi finanziato dalla Commissione europea - CrossJustice (https://site.unibo.it/cross-justice/en), condotto sotto la supervisione dell'Università di Bologna. L'obiettivo del progetto era verificare il livello di attuazione delle sei direttive sui diritti dell'imputato adottate dal 2009 nell'ambito del Programma di Stoccolma. La ricerca ha esaminato criticamente i diritti dell'imputato riconosciuti e tutelati dalla Direttiva 2010/64/UE del 20 ottobre 2010 sul diritto all'interpretazione e alla traduzione; dalla Direttiva 2012/13/UE del 22 maggio 2012 sul diritto all'informazione; la Direttiva 2013/48/UE sul diritto di accesso a un difensore e di informazione di terzi; la Direttiva 2016/343/UE del 9 marzo 2016 sulla presunzione di innocenza e il diritto di presenziare al processo; la Direttiva 2016/800/UE sulle garanzie procedurali per gli imputati minorenni; la Direttiva 2016/1919/UE del 26 ottobre 2016 sul patrocinio a spese dello Stato. I ricercatori coinvolti hanno combinato due diverse metodologie, esaminando la questione sia da una prospettiva tradizionale, condotta da studiosi specializzati in diritto dell'UE e diritto processuale penale nazionale, sia da una nuova analisi computazionale. Nell'ambito di quest'ultimo approccio, la ricerca ha sviluppato una piattaforma di intelligenza artificiale semi-automatizzata, per evidenziare meglio le lacune scoperte dei testi normativi e migliorare l'analisi comparativa tra i sistemi giuridici (https://www.crossjustice.eu/en/index.html#crossjustice-platform)   Il presente contributo si concentra – adottando un metodo tradizionale - sul modo in cui il legislatore italiano ha recepito e attuato le suddette direttive, sia con riferimento alle disposizioni normative sia nell'interpretazione giudiziaria dei vertici del sistema. Infatti, mentre l'acquis dell'UE stabilisce standard minimi comuni in materia di diritti processuali penali, la necessità di promuoverne un'applicazione efficace e coerente rimane particolarmente pressante a causa della forte frammentazione della legislazione nazionale e della relativa giurisprudenza. In termini generali, il quadro che emerge mostra alcuni punti di forza del sistema italiano, con particolare riferimento al diritto al difensore, al diritto all'informazione e alla disclosure (e, in misura meno uniforme, alle regole di esclusione probatoria quando si tratti di tutelare le violazioni delle garanzie difensive). Non mancano tuttavia alcune criticità, spesso legate alla prassi (ad esempio, la necessaria formazione che i difensori degli imputati vulnerabili dovrebbero ricevere, il patrocinio a spese dello Stato, la qualità e l'efficacia del diritto all'interprete e la tradizione degli atti). La presente analisi del sistema italiano, insieme a quella sviluppata per gli altri 10 Stati Membri dell’UE coinvolti nel progetto (Bulgaria, Croazia, Francia, Germania, Paesi Bassi, Polonia, Portogallo, Romania, Spagna, Svezia) ed ai risultati dell’analisi semantica dei testi normativi, fondata su tecniche di Intelligenza Artificiale, ha consentito di sviluppare una ricerca innovativa nei metodi e nei contenuti, che, oltre alla piattaforma Crossjustice, ha trovato recente pubblicazione anche in un volume edito da Brill (Giuseppe Contissa, Giulia Lasagni, Michele Caianiello, Giovanni Sartor (eds.), Effective Protection of the Rights of the Accused in the EU Directives. A Computable Approach to Criminal Procedure Law, 2022)