Giorgio Zauli

IRCCS Ospedale Infantile Burlo Garofolo, Trst, Friuli Venezia Giulia, Italy

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Publications (338)1616.51 Total impact

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    ABSTRACT: Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X‑chromosome inactivation (XCI) studies on the patient's mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 µg/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient's mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X‑linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.
    Molecular Medicine Reports 08/2015; DOI:10.3892/mmr.2015.4215 · 1.48 Impact Factor
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    ABSTRACT: Nanotechnology has opened up the way to the engineering of new organized materials endowed with improved performances. In the past decade, engineered nanoparticles (NPs) have been progressively implemented by exploiting synthetic strategies that yield complex materials capable of performing functions with applications also in medicine. Indeed, in the field of 'nanomedicine' it has been explored the possibility to design multifunctional nanosystems, characterized by high analytical performances and stability, low toxicity and specificity towards a given cell target. Area covered: In this review article, we summarize the advances in the engineering of NPs for biomedical applications, from optical imaging (OI) to multimodal OI and targeted drug delivery. For this purpose, we will provide some examples of how investigations in nanomedicine can support preclinical and clinical research generating innovative diagnostic and therapeutic strategies in oncology. Expert opinion: The progressive breakthroughs in nanomedicine have supported the development of multifunctional and multimodal NPs. In particular, NPs are significantly impacting the diagnostic and therapeutic strategies since they allow the development of: NP-based OI probes containing more than one modality-specific contrast agent; surface functionalized NPs for specific 'molecular recognition'. Therefore, the design and characterization of innovative NP-based systems/devices have great applicative potential into the medical field.
    Expert Opinion on Drug Delivery 08/2015; DOI:10.1517/17425247.2015.1071791 · 4.12 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common lethal human malignancies worldwide and its advanced status is frequently resistant to conventional chemotherapeutic agents and radiation. We evaluated the cytotoxic effect of the orally bioavailable dual PI3K/mTOR inhibitor, NVP-BGT226, on a panel of HCC cell lines, since hyperactivated PI3K/Akt/mTOR signaling pathway could represent a biomolecular target for Small Inhibitor Molecules in this neoplasia. We analyzed the drug activity in both normoxia and hypoxia conditions, the latter playing often a relevant role in the induction of chemoresistance and angiogenesis.In normoxia NVP-BGT226 caused cell cycle arrest in the G0/G1 phase of the cell cycle, induced apoptosis and autophagy at low concentrations. Interestingly the drug inactivated p-Akt and p-S6 at < 10 nM concentration.In hypoxia NVP-BGT226 maintained its cytotoxic efficacy at the same concentration as documented by MTT assays and Western blot analysis. Moreover, the drug showed in hypoxia inhibitory properties against angiogenesis by lowering the expression of the transcription factor HIF-1α and of VEGF.Our results indicate that NVP-BGT226 has a potent cytotoxic effect on HCC cell lines also in hypoxia condition, thus emerging as a potential candidate for cancer treatment in HCC targeted therapy.
    Oncotarget 05/2015; · 6.63 Impact Factor
  • 05/2015; DOI:10.1530/endoabs.37.GP.25.02
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    ABSTRACT: IntroductionTNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily, which plays an important role in regulating cell death and inflammation. Beyond its anti-tumor activity, increasing evidence in animal studies suggests that TRAIL plays a role in the control of autoimmune diseases, and in particular in type 1 diabetes mellitus (T1DM) [1, 2]. In this context, in a previous study carried out in a retrospective cohort of T1DM pediatric patients, we found significant lower levels of circulating TRAIL in T1DM patients with respect to healthy age-matched controls [3]. However, a limitation of our previous study was as follows: (1) the lack of serial serum samples harvested from the same patients at different time post onset and (2) the lack of information about concurrent metabolic status at time of blood sampling.On these bases, the aim of the present study was to analyze the evolution of circulating TRAIL levels in a pilot group of pediatric patients admitted at E ...
    Acta Diabetologica 04/2015; DOI:10.1007/s00592-015-0731-2 · 3.68 Impact Factor
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    ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder in which chemotherapy resistance and refractory relapses occur, with a poorer prognostic outcome.Constitutively active PI3K/Akt/mTOR pathway is a common feature of T-ALL upregulating cell proliferation, survival and drug resistance. This pathway is currently under clinical trials with small molecules inhibitors (SMI).To verify whether a multi-inhibition treatment against Akt protein could enhance the efficacy of individual drug administration and overcome drug resistance as well as to obtain a decrease in single drug concentration, we tested on T-ALL cell lines the effects of combined treatments with three Akt inhibitors with different mode of action, GSK690693, MK-2206 and Perifosine.In cells with hyperactivated Akt, combined administration of the drugs displayed a significant synergistic and cytotoxic effect and affected PI3K/Akt/mTOR pathway at much lower concentration than single drug use. Highest synergistic effect for full inhibition of Akt was also related to the timing of every drug administration. Furthermore the triple treatment had greater efficacy in inducing cell cycle arrest in G0/G1 phase and both apoptosis and autophagy.Targeting Akt as a key protein of PI3K/Akt/mTOR pathway with multiple drugs might represent a new and promising pharmacological strategy for treatment of T-ALL patients.
    Oncotarget 03/2015; · 6.63 Impact Factor
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    ABSTRACT: TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors. In nontransformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may be implicated in the development and progression of diabetes. Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.
    Journal of Immunology Research 02/2015; 2015:680749. DOI:10.1155/2015/680749 · 2.93 Impact Factor
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    ABSTRACT: To evaluate the efficacy of an association of N-acetyl cystein, alpha-lipoic acid, and bromelain (NAC/LA/Br) in the treatment of endometriosis we set up a new in vivo murine model. We explored the anti-inflammatory and proapoptotic effect of this combination on human endometriotic endothelial cells (EECs) and on endothelial cells isolated from normal uterus (UtMECs). We implanted fragments of human endometriotic cysts intraperitoneally into SCID mice to evaluate the efficacy of NAC/LA/Br treatment. UtMECs and EECs, untreated or treated with NAC/LA/Br, were activated with the proinflammatory stimulus TNF-α and their response in terms of VCAM1 expression was evaluated. The proapoptotic effect of higher doses of NAC/LA/Br on UtMECs and EECs was measured with a fluorogenic substrate for activated caspases 3 and 7. The preincubation of EECs with NAC/LA/Br prior to cell stimulation with TNF-α prevents the upregulation of the expression of the inflammatory “marker” VCAM1. Furthermore NAC/LA/Br were able to induce EEC, but not UtMEC, apoptosis. Finally, the novel mouse model allowed us to demonstrate that mice treated with NAC/LA/Br presented a lower number of cysts, smaller in size, compared to untreated mice. Our findings suggest that these dietary supplements may have potential therapeutic uses in the treatment of chronic inflammatory diseases like endometriosis.
    Mediators of Inflammation 01/2015; 2015:1-9. DOI:10.1155/2015/918089 · 3.24 Impact Factor
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    ABSTRACT: TNF-related apoptosis inducing ligand (TRAIL) is an intensively studied cytokine, in particular for its anticancer activity. The discovery that conjunctival sac fluid contains extremely high levels of soluble TRAIL as compared to other body fluids suggested important implications in the context of the immunological surveillance of the eye, in particular of the anterior surface. In this review, we discuss the potential physiopathologic and therapeutic role of the TRAIL/TRAIL receptor system in a variety of ocular cancers. Moreover, since an increasing amount of data has indicated the important biological activities of the TRAIL/TRAIL receptor systems also in a completely different pathologic context such as diabetes mellitus, in the second part of this review we summarize the currently available data on the involvement of TRAIL in the ocular complications of diabetes mellitus as modulator of the inflammatory and angiogenic response in the eye.
    01/2015; 2015:1-8. DOI:10.1155/2015/424019
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    ABSTRACT: By using next generation sequencing, we have analyzed 108 B chronic lymphocytic leukemia (B-CLL) patients. Among genes involved in the TP53 pathway, we found frequent mutations in ATM (n=18), TP53 (n=10) and NOTCH1 (n=10) genes, rare mutations of NOTCH2 (n=2) and CDKN1A/p21 (n=1) and no mutations in BAX, MDM2, TNFRSF10A and TNFRSF10B genes. The in vitro treatment of primary B-CLL cells with the activator of p53 Nutlin-3 induced the transcription of p53 target genes, without significant differences between the B-CLL without mutations and those harboring either ATM or NOTCH1mutations. On the other hand, the subgroup of TP53mutated B-CLL exhibited a significantly lower induction of the p53 target genes in response to Nutlin-3 as compared to the other B-CLL samples. However, among the TP53mutated B-CLL, those showing mutations in the high hot spot region of the DNA binding domain [273-280 aa] maintained a significantly higher p53-dependent transcriptional activity as compared to the other TP53mutated B-CLL samples. Since the ability to elicit a p53-dependent transcriptional activity in vitro has a positive prognostic significance, our data suggest that ATMmutated, NOTCH1mutated and surprisingly, also a subset of TP53mutated B-CLL patients might benefit from therapeutic combinations including small molecule activator of the p53 pathway.
    Oncotarget 12/2014; 5(24):12635-45. · 6.63 Impact Factor
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    ABSTRACT: Ovalbumin (OVA)-sensitized BALB/c mice were i.n. instilled with recombinant TNF-related apoptosis inducing ligand (TRAIL) 24 hours before OVA challenge. The total number of leukocytes and the levels of the chemokine CXCL-1/KC significantly increased in the bronchoalveolar lavage (BAL) fluids of allergic animals with respect to control littermates, but not in the BAL of mice i.n. pretreated with recombinant TRAIL before OVA challenge. In particular, TRAIL pretreatment significantly reduced the BAL percentage of both eosinophils and neutrophils. On the other hand, when TRAIL was administrated simultaneously to OVA challenge its effect on BAL infiltration was attenuated. Overall, the results show that the i.n. pretreatment with TRAIL down-modulated allergic airway inflammation.
    PLoS ONE 12/2014; 9(12):e115387. DOI:10.1371/journal.pone.0115387 · 3.23 Impact Factor
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    ABSTRACT: The anti-leukemic activity of sodium dichloroacetate in p53 mutated/ null cells is mediated by a p53-independent ILF3/p21 pathway This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti-leukemic activity in p53 wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53 mutated B-CLL cells and in p53 mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53 wild-type and p53 mutated B-CLL patient cell cultures, as well as in p53 mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53 null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53 mutated leukemic cells, by acting through the induction of a p53-independent pathway.
    Oncotarget 12/2014; 1. · 6.63 Impact Factor
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    Blood 10/2014; · 10.43 Impact Factor
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    ABSTRACT: The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell growth and survival, and its dysregulation is a reported feature of B-precursor acute lymphoblastic leukemia (B-pre ALL). Torin-2 is a novel, second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2 displayed dramatic antiproliferative activity across a panel of cancer cell lines. To investigate if Torin-2 could represent a new option for the treatment of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of each cell line in a dose-dependent manner, with an IC50 in the nanomolar range. Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G0/G1 phase and affected both mTORC1 and mTORC2 activities as assessed by their specific substrate dephosphorylation. Torin-2 alone suppressed feedback activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway cascade might represent a new promising therapeutic strategy for treatment of B-pre ALL patients.
    Oncotarget 09/2014; 5(20). · 6.63 Impact Factor
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    ABSTRACT: Background Inflammation is believed to link obesity to insulin resistance, as in the setting of metabolic syndrome (MetS). Osteoprotegerin (OPG) is a soluble protein that seems to exert proatherogenic and prodiabetogenic effects. This study aims at determining OPG levels in MetS and whether OPG might contribute to MetS development and progression. Methodology/principal findings Circulating OPG was measured in 46 patients with MetS and 63 controls, and was found significantly elevated in those with MetS. In addition, circulating and tissue OPG was significantly increased in high-fat diet (HFD) fed C57BL6 mice, which is one of the animal models for the study of MetS. To evaluate the consequences of OPG elevation, we delivered this protein to C57BL6 mice, finding that it promoted systemic and adipose tissue proinflammatory changes in association with metabolic abnormalities. Conclusions/significance These data suggest that OPG may trigger adipose tissue proinflammatory changes in MetS/HFD-induced obesity.
    Molecular and Cellular Endocrinology 08/2014; 394(1-2). DOI:10.1016/j.mce.2014.06.004 · 4.24 Impact Factor
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    ABSTRACT: The small molecule inhibitor of the MDM2/p53 interaction Nutlin-3 is a promising anti-cancer agent, which exhibits activity against a variety of cancers, including acute myeloid leukemia (AML). Previous studies have shown that Nutlin-3 variably induces apoptosis and cell cycle arrest in cancer cells while it shows low/absent cytotoxicity in normal cells. However, the reason for the selective pro-apoptotic activity in cancer cells with respect to normal counterparts is incompletely understood. In this study, we have compared the induction of several known target genes of p53 in two p53(wild-type) AML cell lines, OCI-AML3 and MOLM, in comparison with primary normal peripheral blood mononuclear cells (PBMC). Among several p53-target genes activated both in AML cell lines and normal PBMC (BBC3, BAX, MDM2, FAS, CDKN1A, GDF15, GADD45A, TNFRSF10B, TP53I3/PIG3), only TP53I3/PIG3 was selectively activated in MOLM and OCI-AML3, but not in PBMC. The important role of TP53I3/PIG3 in mediating the apoptotic activity of Nutlin-3 was underlined by knock-down experiments with siRNA specific for TP53I3/PIG3, which resulted in a significant decrease in the pro-apoptotic activity of Nutlin-3. © 2012 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 06/2014; 53(6). DOI:10.1002/mc.21985 · 4.77 Impact Factor
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    ABSTRACT: The anti-leukemic activity of the mitochondria-targeting small molecule sodium dichloroacetate (DCA), used alone and in association with the small molecule inhibitor of the p53/MDM2 interaction Nutlin-3, was analyzed in primary B-chronic lymphocytic leukemia (B-CLL) samples (n=22), normal peripheral blood cells (n=10) and in p53wild-type EHEB, JVM-2, JVM-3 B lymphoblastoid cell lines. DCA exhibited a dose-dependent anti-leukemic activity in both primary B-CLL and B leukemic cell lines with a functional p53 status and showed a synergistic cytotoxic activity when used in combination with Nutlin-3. At the molecular level, DCA positively regulated p53 activity, as documented by post-transcriptional modifications of p53 protein and synergized with Nutlin-3 in increasing the expression of the p53-target genes MDM2, PUMA, TIGAR and in particular p21. The potential role of p21 in mediating the DCA+Nutlin-3 anti-leukemic activity was underscored in knocking-down experiments. Indeed, transfection of leukemic cells with p21 siRNAs significantly decreased the DCA+Nutlin-3-induced cytotoxicity. Taken together, our data emphasize that DCA is a molecule that merits to be further evaluated as a chemotherapeutic agent for B-CLL, likely in combination with other therapeutic compounds.
    Oncotarget 05/2014; 5(12). · 6.63 Impact Factor
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    ABSTRACT: A low chronic inflammation mediated by cytokine release is considered a major pathogenic mechanism accounting for the higher risk of cardiovascular disease in the overweight/obese population. In this context, although the existence of a possible interaction between soluble tumor necrosis factor- (TNF-) related apoptosis inducing ligand (TRAIL) and quantity and localization, of adiposity in the body has been hypothesized, no studies have yet investigated this link by radiologic techniques able to assess directly fat mass (FM) in different body regions. To address this issue, we assessed body fat distribution by dual X-rays absorptiometry (DXA) in a sample of 103 women and investigated the possible association between the derived adiposity measures and serum TRAIL concentration. The level of TRAIL showed a positive and independent correlation with arms FM (P < 0.05), trunk FM (P < 0.001) and trunk FM% (P < 0.05), total FM and total FM% (P < 0.001 for both), and an inverse association with legs FM% (P < 0.05). Only trunk FM retained a significant correlation (P < 0.05) with TRAIL after adjusting for all the other indices of regional adiposity. In conclusion, from our study it emerged a significant and independent association of serum TRAIL levels with overall, and, mainly, central adiposity. Further studies are needed to longitudinally investigate the cause-effect relationship between change in body fat distribution and TRAIL.
    Mediators of Inflammation 05/2014; 2014:306848. DOI:10.1155/2014/306848 · 3.24 Impact Factor
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    ABSTRACT: The expression of TRAIL and of its receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4) has been documented in testis, but the presence of soluble TRAIL in seminal fluid, as well as the potential physiopathological role of the TRAIL/TRAIL-R system in spermatozoa, has not been previously investigated. Male donors (n=123) belonging to couples presenting for infertility evaluation were consecutively enrolled in this study. The presence of soluble TRAIL was analyzed in seminal samples by ELISA, while the surface expression of TRAIL receptors was investigated by flow cytometry. High levels of soluble TRAIL were detected in seminal plasma (median: 11621 pg/ml; mean±SD: 13371±8367 pg/ml) and flow cytometric analysis revealed a variable expression of TRAIL receptors in the sperm cellular fraction among different subjects. In addition, the effect of physiologically relevant concentrations of recombinant TRAIL was investigated on survival and motility of spermatozoa. Of interest, the in vitro exposure of capacitated spermatozoa to recombinant TRAIL (10 ng/ml) significantly preserved their overall survival. Therefore, the present study documents for the first time the presence of elevated levels of the anti-inflammatory cytokine TRAIL in seminal fluids. Moreover, the demonstration that recombinant TRAIL promotes spermatozoa survival after capacitation suggests potential therapeutic implications.
    Reproduction 05/2014; DOI:10.1530/REP-14-0144
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    ABSTRACT: Dye-doped near infrared-emitting silica nanoparticles (DD-NIRsiNPs) represent a valuable tool in bioimaging, because they provide sufficient brightness, resistance to photobleaching and consist of hydrophilic non-toxic materials. Here, we report the development of multiple dye-doped NIR emitting siNPs (mDD-NIRsiNPs), based on silica–PEG core–shell nanostructures doped with a donor–acceptor couple, exhibiting a tunable intensity profile across the NIR spectrum and suitable for both multiparametric flow cytometry analyses and time-domain optical imaging. In order to characterize the optical properties and fluorescence applications of the mDD-NIRsiNPs, we have characterized their performance by analyzing their in vivo biodistribution in healthy mice as well as in lymphoma bearing xenografts, and their suitability as contrast imaging agents for cell labeling and tracking. The mDD-NIRsiNPs features will be useful in designing new applications for imaging agents based on silica nanoparticles for different experimental disease models.
    RSC Advances 04/2014; 4(35). DOI:10.1039/C4RA01535E · 3.84 Impact Factor

Publication Stats

8k Citations
1,616.51 Total Impact Points

Institutions

  • 2010–2015
    • IRCCS Ospedale Infantile Burlo Garofolo
      Trst, Friuli Venezia Giulia, Italy
  • 1993–2013
    • Universita degli studi di Ferrara
      • Department of Morphology, Surgery and Experimental Medicine
      Ferrara, Emilia-Romagna, Italy
  • 2008
    • University of Udine
      • Department of Medical and Biological Sciences
      Udine, Friuli Venezia Giulia, Italy
  • 2002–2008
    • Università degli Studi di Trieste
      • Department of Life Sciences
      Trst, Friuli Venezia Giulia, Italy
  • 2000–2008
    • Università degli Studi G. d'Annunzio Chieti e Pescara
      Chieta, Abruzzo, Italy
    • Università degli Studi di Brescia
      Brescia, Lombardy, Italy
  • 2007
    • Università degli studi di Cassino e del Lazio Meridionale
      Cassino, Latium, Italy
  • 1989–2006
    • University of Bologna
      • • Section of Microbiology and Virology
      • • Institute of Haematology
      • • School of Medicine
      Bolonia, Emilia-Romagna, Italy
  • 2004
    • Università degli studi di Parma
      • Department of Clinical and Experimental Medicine
      Parma, Emilia-Romagna, Italy
  • 2001
    • University of Catania
      Catania, Sicily, Italy
  • 1997–1999
    • University of Maryland, Baltimore
      • Institute of Human Virology
      Baltimore, Maryland, United States
    • National Cancer Institute (USA)
      • Laboratory of Cell Biology
      베서스다, Maryland, United States
  • 1998
    • Beth Israel Deaconess Medical Center
      • Division of Signal Transduction
      Boston, MA, United States
  • 1995
    • Johns Hopkins Bloomberg School of Public Health
      Baltimore, Maryland, United States