Wage dispersion in Italy: An exploration based on linked employer-employee data

This article analyzes wage dispersion in a sample of Italian firms, by taking advantage of a unique Linked Employer-Employee dataset (LEED) merging four data sources from the National Institute of Statistics. An in-depth descriptive analysis conveys that knowledge-intensive services record the highest within- and between-firms wage dispersion in the sample. Regression-based results show that innovation does not drive up inequality in large companies. However, it can contribute to enlarge the within-firm wage dispersion as well as the wage gap across small firms. Overall, we argue that institutional factors should be called upon to explain the dramatic increase in wage disparities in the Italian economy

Autoxidation Products of the Methanolic Extract of the Leaves of Combretum micranthum Exert Antiviral Activity against Tomato Brown Rugose Fruit Virus (ToBRFV)

open7noTomato brown rugose fruit virus (ToBRFV) is a new damaging plant virus of great interest from both an economical and research point of view. ToBRFV is transmitted by contact, remains infective for months, and to-date, no resistant cultivars have been developed. Due to the relevance of this virus, new effective, sustainable, and operator-safe antiviral agents are needed. Thus, 4- hydroxybenzoic acid was identified as the main product of the alkaline autoxidation at high temperature of the methanolic extract of the leaves of C. micranthum, known for antiviral activity. The autoxidized extract and 4-hydroxybenzoic acid were assayed in in vitro experiments, in combination with a mechanical inoculation test of tomato plants. Catechinic acid, a common product of rearrangement of catechins in hot alkaline solution, was also tested. Degradation of the viral particles, evidenced by the absence of detectable ToBRFV RNA and the loss of virus infectivity, as a possible consequence of disassembly of the virus coat protein (CP), were shown. Homology modeling was then applied to prepare the protein model of ToBRFV CP, and its structure was optimized. Molecular docking simulation showed the interactions of the two compounds, with the amino acid residues responsible for CP-CP interactions. Catechinic acid showed the best binding energy value in comparison with ribavirin, an anti-tobamovirus agent.openValeria Iobbi, Anna Paola Lanteri, Andrea Minuto, Valentina Santoro, Giuseppe Ferrea, Paola Fossa, Angela BisioIobbi, Valeria; Paola Lanteri, Anna; Minuto, Andrea; Santoro, Valentina; Ferrea, Giuseppe; Fossa, Paola; Bisio, Angel

Leupaxin Expression Is Dispensable for B Cell Immune Responses.

The generation of a potent humoral immune response by B cells relies on the integration of signals induced by the B cell receptor, toll-like receptors and both negative and positive co-receptors. Several reports also suggest that integrin signaling plays an important role in this process. How integrin signaling is regulated in B cells is however still partially understood. Integrin activity and function are controlled by several mechanisms including regulation by molecular adaptors of the paxillin family. In B cells, Leupaxin (Lpxn) is the most expressed member of the family and in vitro studies suggest that it could dampen BCR signaling. Here, we report that Lpxn expression is increased in germinal center B cells compared to naïve B cells. Moreover, Lpxn deficiency leads to decreased B cell differentiation into plasma cells in vitro. However, Lpxn seems dispensable for the generation of a potent B cell immune response in vivo. Altogether our results suggest that Lpxn is dispensable for T-dependent and T-independent B cell immune responses

Early Detection of External Neurological Symptoms through a Wearable Smart-Glasses Prototype

The Internet of Things (IoT) framework is moving the research community to provide smart systems and solutions aimed at revolutionizing medical sciences and healthcare. Given the extreme diffusion of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the demand for a solution to early detect neurological symptoms of such diseases strongly arose. According to the medical literature, such early detection can be obtained through the correlation between PD and AD and some external symptoms: the Essential Tremor (ET) and the number of Eye Blinks (EBs). In this paper, which can be considered as an extended version of [1], we present a prototype of wearable smart glasses able to detect the presence of ET of the head and to count the number of EBs at the same time, in a transparent way with respect to the final user. Numerical results demonstrate the reliability of the proposed approach: the proposed algorithms are able to i) correctly recognize the ET with an overall accuracy above 97% and ii) count the number of EBs with an overall error around 9%

CREB engages C/EBPδ to initiate leukemogenesis.

cAMP response element binding protein (CREB) is frequently overexpressed in acute myeloid leukemia (AML) and acts as a proto-oncogene; however, it is still debated whether such overactivation alone is able to induce leukemia as its pathogenetic downstream signaling is still unclear. We generated a zebrafish model overexpressing CREB in the myeloid lineage, which showed an aberrant regulation of primitive hematopoiesis, and in 79% of adult CREB-zebrafish a block of myeloid differentiation, triggering to a monocytic leukemia akin the human counterpart. Gene expression analysis of CREB-zebrafish revealed a signature of 20 differentially expressed human homologous CREB targets in common with pediatric AML. Among them, we demonstrated that CREB overexpression increased CCAAT-enhancer-binding protein-δ (C/EBPδ) levels to cause myeloid differentiation arrest, and the silencing of CREB-C/EBPδ axis restored myeloid terminal differentiation. Then, C/EBPδ overexpression was found to identify a subset of pediatric AML affected by a block of myeloid differentiation at monocytic stage who presented a significant higher relapse risk and the enrichment of aggressive signatures. Finally, this study unveils the aberrant activation of CREB-C/EBPδ axis concurring to AML onset by disrupting the myeloid cell differentiation process. We provide a novel in vivo model to perform high-throughput drug screening for AML cure improvement

Benznidazole treatmentof Chagasic encephalitis in pregnant women with AIDS

We report a case of chagasic meningoencephalitis reactivation in a pregnant woman co-infected with Trypanosoma cruzi and HIV that was successfully managed with benznidazole and highly active antiretroviral therapy. Early diagnosis enabled rapid specific treatment that improved the health of the patient and her baby.Fil: Bisio, Margarita María Catalina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lattner, Jorge. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Fink, Valeria. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Burgos, Juan Miguel. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garcia Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Freilij, Hector León. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentin

Exploring the Anticancer Potential of Premna resinosa (Hochst.) Leaf Surface Extract: Discovering New Diterpenes as Heat Shock Protein 70 (Hsp70) Binding Agents

Premna, a genus consisting of approximately 200 species, predominantly thrives in tropical and subtropical areas. Many of these species have been utilized in ethnopharmacology for diverse medicinal applications. In Saudi Arabia, Premna resinosa (Hochst.) Schauer (Lamiaceae) grows wildly, and its slightly viscid leaves are attributed to the production of leaf accession. In this study, we aimed to extract the surface accession from fresh leaves using dichloromethane to evaluate the anticancer potential. The plant exudate yielded two previously unknown labdane diterpenes, Premnaresone A and B, in addition to three already described congeners and four known flavonoids. The isolation process was accomplished using a combination of silica gel column chromatography and semi preparative HPLC, the structures of which were identified by NMR and HRESIMS analyses and a comparison with the literature data of associated compounds. Furthermore, we employed a density functional theory (DFT)/NMR approach to suggest the relative configuration of different compounds. Consequently, we investigated the possibility of developing new chaperone inhibitors by subjecting diterpenes 1–5 to a Surface Plasmon Resonance-screening, based on the knowledge that oridonin, a diterpene, interacts with Heat Shock Protein 70 (Hsp70) 1A in cancer cells. Additionally, we studied the anti-proliferative activity of compounds 1–5 on human Jurkat (human T-cell lymphoma) and HeLa (epithelial carcinoma) cell lines, where diterpene 3 exhibited activity in Jurkat cell lines after 48 h, with an IC50 of 15.21 ± 1.0 µM. Molecular docking and dynamic simulations revealed a robust interaction between compound 3 and Hsp70 key residues

Pediatric AML: from prognostic biomarkers to functional characterization

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by recurrent genetic aberrations. The prognosis of childhood AML has significantly improved over the last two decades, nevertheless the 30% of cases still relapse1–3. Intensive efforts have been devoted to identify new genetic abnormalities and altered signalling pathways to better stratify patients in different risk classes in order to improve children survival treating them with a more specific therapy. However still half of the AML cases do not present a recurrent genetic aberration. Thus, during this PhD I focused on the identification of new molecular markers at diagnosis and the evaluation of known markers during the disease follow up. The prognostic value of these markers has been evaluated to improve patients stratification and whenever possible to suggest novel tailored treatments. The overall goal of this study was also to functionally dissect the leukemogenic mechanism of action of these new molecular markers, in order to find suitable candidate gene/pathway to be targeted in novel personalized therapies. Initially, a screening of new markers at diagnosis was performed in a large Italian cohort of pediatric AML defining the incidence of genetic abnormalities previously described as single case reports or as novel rearrangements identified by next-generation sequencing. The del(4)(q12)FIP1L1-PDGFRA, t(16;21)(p11;q22)FUS-ERG, t(8;16)(p11;p13)MOZ-CB, t(11;17)(q23;q12-21)MLL-AF17, t(4;11)(q35;q23)MLL-ARGB2, t(3;5)(q25;q34)NPM1-MLF1, MLLPTD, and t(11;17)(p15.5;p13)NUP98-PHF23 were finally classified to be rare events at diagnosis. An exception was the translocation t(5;11)(q35;p15.5)NUP98-NSD1 which reached an incidence of 4% and was found to occur together with FLT3-ITD mutation in more than 50% of cases. Then, the mutations of the oncogene c-KIT were taken into evaluation in a selected subset of CBF-rearranged patients since these abnormalities were previously reported to be frequent in adults with CFB-AML at diagnosis4. I defined a high frequency of c-KIT mutations for RUNX1-RUNX1T1 (25%) and for CBFB-MYH11 (18.5%) rearranged pediatric patients. Prognostic value of c-KIT mutations was determined only for the RUNX1-RUNX1T1 rearranged patients, suggesting that they could be further evaluated for a targeted therapy with tyrosine kinase inhibitors. Then, I take into consideration the evaluation of a molecular marker detected at diagnosis during therapy course, by evaluating the role of monitoring the minimal residual disease (MRD) by Real time RQ-PCR . In pediatric AML, post-treatment MRD monitoring of biomarkers has been rarely used in the clinical management of patients:. molecular markers suitable for MRD detection still remains debated. I improved knowledge for patients with AML1-ETO rearrangement and in FLT3-ITD mutation, revealing that MRD levels after induction chemotherapy were prognostically significant in identifying those with higher risk to relapse and die These new group of patients , within the same genetic subgroup, may benefit of novel risk stratification or pre-emptive therapy strategies supporting the t(8;21) and FLT3-ITD as reliable molecular markers for disease monitoring also during follow up. A large part of this PhD program was committed to dissect the biology of some recurrent aberrancies being their functional role investigation mandatory to develop new targeted therapies to improve children cure. I hypothesized that biology might explain the difference in therapy response highlighted in the MRD study performed on FLT3-ITDpatientswhere half of them was found to reduce MRD levels less than 2 logs from diagnosis with a consequent high risk of relapse and death. By gene expression analyses , I showed that these patients had a different gene expression profile related to epigenetic control, most concerning methylation and acetylation of histones. These findings may suggest that the use of epigenetic drugs, combined with conventional strategies, could be a new therapeutic opportunity for a the FLT3-ITD patients showing high MRD levels after the end of first induction course. A second functional study was carried on the t(6;11)(q27;q23)MLL-AF6 rearrangement. In the Italian AML cohort, 10% of AML patients are MLL-rearranged5 and among them the t(6;11) cases present the worst prognosis5,6. By in vitro studies, I found that wild type AF6 protein co-localized with RAS in the bone marrow of healthy donors, while AF6 was sequestered into the nucleus provoking RAS overactivation in t(6;11)(q27;q23) rearranged AML. The role of AF6 in RAS inhibition was confirmed by AF6 silencing or treatment with RAS antagonists, revealing the implication of RAS pathway in the aggressiveness of MLL-AF6 leukemia. This discovery confirmed the usefulness of Tipifarnib, a drug currently used in RASopathies7, in this AML subgroup, and opens for new targeted therapies to overcome their poor outcome. The third functional study was performed on a gene recently found implicated in several translocations being not rare (4.6%) in pediatric AML at diagnosis and with outcome severe prognosis, NUP988–10. I deep inside the biology of all the NUP98 detected rearrangements, and identified a specific gene expression pattern as well as a typical outcome. Gene ontology revealed an enrichment in biological processes linked to the nuclear organization and chromosome instability, confirmed also by in vitro studies on NUP98-NSD1 rearranged primary cells. Moreover, I reported CREB control in the transcription of NUP98 and consequently of its chimeras. Altogether, these findings open for further studies into the leukemogenic mechanism of NUP98-rearranged AML, and highlight CREB as a possible therapeutic target to decrease the oncogenic properties of NUP98-chimeras. Finally, during this PhD a variety of molecular lesions were identified permitting a more detailed diagnosis for pediatric AML. The prognostic significance of each marker was evaluated and included in the risk classes stratification of the new AIEOP LAM 2013 protocol, conferring to genetics a strong role in guiding therapeutic strategies. Functional studies were able to characterize new candidate genes that can be specific for a subgroups of AML patients with detrimental prognosis, to be further studied for their therapeutic role and when possible for a even more personalized therapy. All together, this work achieved results that are currently translated into clinical management, and will contribute to the improvement of the outcome of AML children.La leucemia acuta mieloide (LAM) è una malattia geneticamente eterogenea,caratterizzata da ricorrenti anomalie molecolari. Nonostante la prognosi dei pazienti pediatrici affetti da LAM sia notevolmente migliorata negli ultimi anni, il tasso di ripresa di malattia è di circa il 30% 1–3. Numerosi studi sono emersi per identificare nuove anomalie genetiche o vie di segnale deregolate nella LAM pediatrica al fine di migliorare la stratificazione dei pazienti nelle diverse classi di rischio, e di conseguenza poter adottare dei percorsi terapeutici specifici e più mirati. Ad oggi tuttavia, per circa il 50% dei casi non si trova alla diagnosi un marcatore molecolare noto in grado di garantire una corretta stratificazione del paziente. Per tale ragione il mio dottorato di ricerca ha avuto come primo scopo la ricerca e l’identificazione di nuovi marcatori molecolari alla diagnosi , e di studiarne il ruolo prognostico affinché si possa garantire una più corretta diagnosi a un più alto numero di pazienti, e si possa valutarne in caso un ruolo anche come marker di monitoraggi durante la terapia del paziente. Infine, allo scopo puramente diagnostico, è stato abbinato uno scopo di ricerca di base, cioè caratterizzare il processo neoplastico mediato da alcuni di questi marcatori molecolari, cercando di identificare dei geni malattia che possano servire essere dei candidati target terapeutici, utili a porre le basi per una gestione sempre più personalizzata e quindi efficace della terapia. Inizialmente ho effettuato una serie di screening molecolari con l’intento di valutare l'incidenza di alcune anomalie genetiche precedentemente conosciute solo tramite case report o identificate tramite sequenziamento massivo dell’RNA. In particolare, ho definito la del(4)(q12)FIP1L1-PDGFRA, la t(16;21)(p11;q22)FUS-ERG, la t(8;16)(p11;p13)MOZ-CBP, la t(11;17)(q23;q12-21)MLL-AF17, t(4;11)(q35;q23)MLL-ARGB2, la t(3;5)(q25;q34)NPM1-MLF1, il MLLPTD, e la t(11;17)(p15.5;p13)NUP98-PHF23 come eventi mutazionali rari nella coorte pediatrica italiana arruolata nel protocollo LAM 2001-02 (totale pazienti N=482). Al contrario, la t(5;11)(q35;p15.5)NUP98-NSD1 è stata riscontrata avvenire con una frequenza del 4%, e spesso in concomitanza alla mutazione FLT3-ITD (nel 50% dei casi). Tale traslocazione è stata inoltre valutata per il suo peso prognostico, rivelandosi un fattore prognostico negativo perché associato ad un elevato rischio di recidiva e morte. Poi, un altro screening ha riguardato la valutazione delle presenza di mutazioni a carico del gene c-KIT, in un gruppo di pazienti già con riarrangiamento del CBF. Le mutazioni di questo recettore delle tirosin chinasi sono già state ampiamente descritte in numerosi studi soprattutto riguardanti pazienti adulti affetti da LAM4. I risultati confermano un’alta frequenza di mutazione di c-KIT anche nei pazienti pediatrici con t(8;21)RUNX1-RUNX1T1 (25%) e con inv(16)CBFB-MYH11 ( 18.5%). Il valore prognostico negativo è risultato significativo solo nel gruppo con RUNX1-RUNX1T1, per i quali, l’identificazione di queste mutazioni potrebbero supportare l’uso di eventuali terapie con inibitori delle tirosin chinasi per migliorare la loro cura. Oltre alla diagnosi, il marcatore molecolare può avere un ruolo fondamentale anche durante il corso della malattia. Mi sono occupata di mettere a punto lo studio della malattia residua minima (MRM) mediante PCR quantitativa per tre importanti marker ricorrenti nelle LAM pediatriche. Ad oggi, il monitoraggio della MRM nella LAM pediatrica è scarsamente utilizzato. Qui, si propone il monitoraggio della MRM tramite la RQ-PCR dopo chemioterapia di induzione nei pazienti con t(8;21) e FLT3-ITD in grado di individuare i pazienti a più alto rischio di recidivare. Aver identificato la t(8;21) e FLT3-ITD come buoni marcatori molecolari per il monitoraggi della MRM, consentirà ai clinici di poter valutare delle strategie alternative in quei pazienti che potrebbero beneficiare di terapie farmacologiche supplementari al fine di evitare la ripresa della malattia. Infine, molto tempo del mio dottorato è stato impegnato alla caratterizzazione biologica e funzionale di alcuni marcatori molecolari ricorrenti con il fine ultimo di identificare nuovi possibili target terapeutici per migliorare la cure e la sopravvivenza dei pazienti. In primis, ipotizzando che la diversa risposta terapeutica dei casi FLT3-ITD abbia origine da una diversità biologia, abbiamo effettuato delle analisi di espressione genica su questo gruppo di pazienti. Questo studio ha permesso di identificare un profilo di espressione genica caratteristico per i pazienti che riducendo meno la malattia dopo l’induzione vanno incontro a un più alto rischio di ricadere. I processi biologici arricchiti in questi pazienti sono risultati riguardare la metilazione e l’acetilazione degli istoni, suggerendo che eventuali agenti deacentilanti o demetilanti, in combinazione con la terapia convenzionale, possano migliorare la sopravvivenza libera da avventi avversi di questi pazienti. Un altro studio funzionale ha preso in esame la t(6;11)(q27;q23)MLL-AF6. Circa il 10% della popolazione pediatrica italiana presenta uno dei riarrangiamenti a carico del gene MLL , tra questi la t(6;11) presenta la prognosi peggiore5,6. Attraverso studi in vitro, ho rivelato che la proteina AF6 endogena si localizza nel citoplasma insieme all’oncogene RAS in cellule di midollo osseo sano. Viceversa, nei pazienti con traslocazione t(6;11), AF6 è stato riscontrato essere nel nucleo impedendo il fisiologico controllo di RAS nel citoplasma, comportandone un’iper-attivazione della via. Sia il silenziamento di AF6 sia il trattamento con inibitori di RAS hanno confermato il ruolo chiave del pathway di RAS nel sostenere l’aggressività di questa leucemia. Infine, lo studio ha comprovato il Tipifarnib, farmaco già in uso nelle RASopatie7, come nuovo farmaco utilizzabile nei pazienti pediatrici con t(6;11). Il terzo studio funzionale ha riguardato un gene molto nuovo nella LAM pediatrica, il gene NUP98. Le traslocazioni somatiche associate a questo gene8–10 si sono riscontrate non rare nella corte pediatrica LAM italiana (4.6%). Lo studio più funzionale ha poi chiarito che ciascuna di queste traslocazioni identificate una diversa biologia così come un diverso ruolo prognostico . Grazie all’analisi di espressione genica ho identificato l’instabilità genetica come il processo biologico maggiormente deregolato in questo gruppo di pazienti con NUP98-LAM. Tale processo è stato verificato in vitro grazie a colture cellulari primarie di pazienti NUP98-NSD1 riarrangiati. Inoltre, ho dimostrato che il fattore di trascrizione CREB controlla la trascrizione del gene NUP98, cosi come di tutte le oncoproteine che si riscontrano nelle LAM mantenere l’N terminale dello stesso. Questi risultati identificano il ruolo funzionale della chimera NUP98-NSD1, e candidano CREB a possibile bersaglio terapeutico per combattere l’espressione della chimera e quindi la progressione della malattia . In conclusione, durante i tre anni di dottorato di ricerca ho caratterizzato una serie di marcatori molecolari che hanno permesso una migliore e più dettagliata stratificazione dei pazienti alla diagnosi. Dato il valore prognostico dei vari marcatori, essi sono stati inclusi nel nuovo protocollo terapeutico LAM 2013, che conferisce alla genetica molecolare un ruolo determinante nel guidare la terapia. Infine gli studi funzionali hanno finora portato all‘identificazione di nuovi target specifici in vari sottogruppi di LAM a prognosi infausta. Studi futuri sono in corso per valutare questi biomarcatori come target terapeutici da utilizzare per incrementare le possibilità di curare i bambini affetti da LAM

Leupaxin Expression Is Dispensable for B Cell Immune Responses

The generation of a potent humoral immune response by B cells relies on the integration of signals induced by the B cell receptor, toll-like receptors and both negative and positive co-receptors. Several reports also suggest that integrin signaling plays an important role in this process. How integrin signaling is regulated in B cells is however still partially understood. Integrin activity and function are controlled by several mechanisms including regulation by molecular adaptors of the paxillin family. In B cells, Leupaxin (Lpxn) is the most expressed member of the family and in vitro studies suggest that it could dampen BCR signaling. Here, we report that Lpxn expression is increased in germinal center B cells compared to naïve B cells. Moreover, Lpxn deficiency leads to decreased B cell differentiation into plasma cells in vitro. However, Lpxn seems dispensable for the generation of a potent B cell immune response in vivo. Altogether our results suggest that Lpxn is dispensable for T-dependent and T-independent B cell immune responses