Publications by authors named "Arcangelo Liso"

67 Publications

The Significance of Purity: Leukaemias Involving the Erythroid Lineage.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020077. Epub 2020 Nov 1.

Fondazione Policlinico Universitario A. Gemelli IRCCS - Istituto di Ematologia, Università Cattolica del Sacro Cuore, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4084/MJHID.2020.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643776PMC
November 2020

Insulin-Like Growth Factor Binding Protein 6 Is Secreted in Extracellular Vesicles upon Hyperthermia and Oxidative Stress in Dendritic Cells But Not in Monocytes.

Int J Mol Sci 2020 Jun 22;21(12). Epub 2020 Jun 22.

Department of Medical and Surgical Sciences, University of Foggia, Via Napoli 121, 71122 Foggia, Italy.

Recently, insulin-like growth factor binding protein 6 (IGFBP-6) has been shown to play a putative role in the immune system, as monocyte-derived dendritic cells (Mo-DCs) are stimulated by hyperthermia to express IGFBP-6 at both the mRNA and protein levels. However, the presence of IGFBP-6 in extracellular vesicles (EVs) and whether other pro-inflammatory stimuli can induce IGFBP-6 expression in Mo-DCs are not known yet. In this brief report, we show that hyperthermia (39 °C) induces IGFBP-6 secretion associated with microvesicles and exosomes as early as 3 h. Moreover, free IGFBP-6 is found in conditioned media (CM) of hyperthermia- and HO-treated Mo-DCs, but not in CM obtained from monocytes similarly treated. These results show that diverse inflammatory stimuli can induce IGFBP-6 association with EVs and secretion in conditioned medium, indicating a role for IGFBP-6 in communication between immune cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21124428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352465PMC
June 2020

Proteasome Inhibitors as a Possible Therapy for SARS-CoV-2.

Int J Mol Sci 2020 May 20;21(10). Epub 2020 May 20.

Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy.

The COVID-19 global pandemic is caused by SARS-CoV-2, and represents an urgent medical and social issue. Unfortunately, there is still not a single proven effective drug available, and therefore, current therapeutic guidelines recommend supportive care including oxygen administration and treatment with antibiotics. Recently, patients have been also treated with off-label therapies which comprise antiretrovirals, anti-inflammatory compounds, antiparasitic agents and plasma from convalescent patients, all with controversial results. The ubiquitin-proteasome system (UPS) is important for the maintenance of cellular homeostasis, and plays a pivotal role in viral replication processes. In this review, we discuss several aspects of the UPS and the effects of its inhibition with particular regard to the life cycle of the coronaviruses (CoVs). In fact, proteasome inhibition by various chemical compounds, such as MG132, epoxomycin and bortezomib, may reduce the virus entry into the eucariotic cell, the synthesis of RNA, and the subsequent protein expression necessary for CoVs. Importantly, since UPS inhibitors reduce the cytokine storm associated with various inflammatory conditions, it is reasonable to assume that they might be repurposed for SARS-CoV-2, thus providing an additional tool to counteract both virus replication as well as its most deleterious consequences triggered by abnormal immunological response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21103622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279248PMC
May 2020

Evaluation of the Potential of Biofilm Formation of subsp. and as Competitive Biocontrol Agents Against Pathogenic and Food Spoilage Bacteria.

Microorganisms 2020 Jan 25;8(2). Epub 2020 Jan 25.

Department of the Science of Agriculture, Food and Environment (SAFE), University of Foggia, Via Napoli 25, 71122 Foggia, Italy.

This study proposes to exploit the in vivo metabolism of two probiotics ( subsp. and ) which, upon adhesion on a solid surface, form a biofilm able to control the growth of pathogenic and food spoilage bacteria. The results showed that pathogenic cell loads were always lower in presence of biofilm (6.5-7 log CFU/cm) compared to those observed in its absence. For O157:H7, a significant decrease (>1-2 logarithmic cycles) was recorded; for , and , cell load reductions ranged from 0.5 to 1.5 logarithmic cycles. When tested as active packaging, the biofilm was successfully formed on polypropylene, polyvinyl chloride, greaseproof paper, polyethylene and ceramic; the sessile cellular load ranged from 5.77 log CFU/cm (grease-proof paper) to 6.94 log CFU/cm (polyethylene, PE). To test the potential for controlling the growth of spoilage microorganisms in food, soft cheeses were produced, inoculated with and wrapped in PE pellicles with pre-formed biofim, packed both in air and under vacuum, and stored at 4 and 15 °C: an effective effect of biofilms in slowing the decay of the microbiological quality was recorded.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/microorganisms8020177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074751PMC
January 2020

From fever to immunity: A new role for IGFBP-6?

J Cell Mol Med 2018 10 17;22(10):4588-4596. Epub 2018 Aug 17.

Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

Fever is a fundamental response to infection and a hallmark of inflammatory disease, which has been conserved and shaped through millions of years of natural selection. Although fever is able to stimulate both innate and adaptive immune responses, the very nature of all the molecular thermosensors, the timing and the detailed mechanisms translating a physical trigger into a fundamental biological response are incompletely understood. Here we discuss the consequence of hyperthermic stress in dendritic cells (DCs), and how the sole physical input is sensed as an alert stimulus triggering a complex transition in a very narrow temporal window. Importantly, we review recent findings demonstrating the significant and specific changes discovered in gene expression and in the metabolic phenotype associated with hyperthermia in DCs. Furthermore, we discuss the results that support a model based on a thermally induced autocrine signalling, which rewires and sets a metabolism checkpoint linked to immune activation of dendritic cells. Importantly, in this context, we highlight the novel regulatory functions discovered for IGFBP-6 protein: induction of chemotaxis; capacity to increase oxidative burst and degranulation of neutrophils, ability to induce metabolic changes in DCs. Finally, we discuss the role of IGFBP-6 in autoimmune disease and how novel mechanistic insights could lead to exploit thermal stress-related mechanisms in the context of cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.13738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156343PMC
October 2018

Use of design of experiments to optimize the production of microbial probiotic biofilms.

PeerJ 2018 10;6:e4826. Epub 2018 Jul 10.

Department of the Science of Agriculture, Food and Environment (SAFE), University of Foggia, Foggia, Italy.

Here, we describe the production of a probiotic biofilm through three intermediate steps: (1) measurement of the adhesion capacity of 15 probiotic strains to evaluate their tendency to form biofilm on different surfaces (stainless steel, glass, and polycarbonate); (2) evaluation of the effects of pH, temperature, cellular growth phase, agitation, and presence of surfactants on probiotic biofilm formation (BF) through the Design of Experiments (DoE) approach; (3) study of the effects of pH, temperature and surfactants concentration on probiotic BF using the Central Composite Design. Finally, we show that biofilms pre-formed by selected probiotics can delay the growth of pathogens, such as chosen as model organism. Among the tested strains, DSM20088 and DSM20016 were found to be as the probiotics able to ensure the greatest adhesion (over 6 Log CFU cm) to the surfaces tested in a very short time (<24 h). Cellular growth phase and agitation of the medium were factors not affecting BF, pH exerted a very bland effect and a greater tendency to adhesion was observed when the temperature was about 30 °C. The results obtained in the last experimental phase suggest that our probiotic biofilms can be used as an efficient mean to delay the growth of : the λ phase length, in fact, was longer in samples containing probiotic biofilms (0.30-1.02 h) against 0.08 h observed in the control samples. A reduction of the maximum cell load was also observed (6.99-7.06 Log CFU mL against about 8 Log CFU mL observed in the control samples).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7717/peerj.4826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044272PMC
July 2018

Febrile temperature reprograms by redox-mediated signaling the mitochondrial metabolic phenotype in monocyte-derived dendritic cells.

Biochim Biophys Acta Mol Basis Dis 2018 Mar 12;1864(3):685-699. Epub 2017 Dec 12.

Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. Electronic address:

Fever-like hyperthermia is known to stimulate innate and adaptive immune responses. Hyperthermia-induced immune stimulation is also accompanied with, and likely conditioned by, changes in the cell metabolism and, in particular, mitochondrial metabolism is now recognized to play a pivotal role in this context, both as energy supplier and as signaling platform. In this study we asked if challenging human monocyte-derived dendritic cells with a relatively short-time thermal shock in the fever-range, typically observed in humans, caused alterations in the mitochondrial oxidative metabolism. We found that following hyperthermic stress (3h exposure at 39°C) TNF-α-releasing dendritic cells undergo rewiring of the oxidative metabolism hallmarked by decrease of the mitochondrial respiratory activity and of the oxidative phosphorylation and increase of lactate production. Moreover, enhanced production of reactive oxygen and nitrogen species and accumulation of mitochondrial Ca was consistently observed in hyperthermia-conditioned dendritic cells and exhibited a reciprocal interplay. The hyperthermia-induced impairment of the mitochondrial respiratory activity was (i) irreversible following re-conditioning of cells to normothermia, (ii) mimicked by exposing normothermic cells to the conditioned medium of the hyperthermia-challenged cells, (iii) largely prevented by antioxidant and inhibitors of the nitric oxide synthase and of the mitochondrial calcium porter, which also inhibited release of TNF-α. These observations combined with gene expression analysis support a model based on a thermally induced autocrine signaling, which rewires and sets a metabolism checkpoint linked to immune activation of dendritic cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2017.12.010DOI Listing
March 2018

Insulin-like growth factor-6 (IGFBP-6) stimulates neutrophil oxidative burst, degranulation and chemotaxis.

Inflamm Res 2018 Feb 30;67(2):107-109. Epub 2017 Oct 30.

Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

The aim of this study was to understand whether insulin-like growth factor-binding protein-6 (IGFBP-6) has functional effects on neutrophils, in particular when they cross epithelium during inflammation. We found that IGFBP-6 increased ROS production (cytofluorimetry), degranulation of primary and tertiary granules (ELISA) and transmigration through the epithelial monolayer. No priming by IGFBP-6 on neutrophils stimulated by either PMA or fMLP was observed. IGFBP-6 is an agonist of neutrophils' functions, most likely when these cells have been already activated by other stimuli.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00011-017-1107-6DOI Listing
February 2018

Human monocyte-derived dendritic cells exposed to hyperthermia show a distinct gene expression profile and selective upregulation of .

Oncotarget 2017 Sep 1;8(37):60826-60840. Epub 2017 Jun 1.

Institute of Haematology, University of Perugia, Perugia, Italy.

Fever plays a role in activating innate immunity while its relevance in activating adaptive immunity is less clear. Even brief exposure to elevated temperatures significantly impacts on the immunostimulatory capacity of dendritic cells (DCs), but the consequences on immune response remain unclear. To address this issue, we analyzed the gene expression profiles of normal human monocyte-derived DCs from nine healthy adults subjected either to fever-like thermal conditions (39°C) or to normal temperature (37°C) for 180 minutes. Exposure of DCs to 39°C caused upregulation of 43 genes and downregulation of 24 genes. Functionally, the up/downregulated genes are involved in post-translational modification, protein folding, cell death and survival, and cellular movement. Notably, when compared to monocytes, DCs differentially upregulated transcription of the secreted protein IGFBP-6, not previously known to be specifically linked to hyperthermia. Exposure of DCs to 39°C induced apoptosis/necrosis and resulted in accumulation of IGFBP-6 in the conditioned medium at 48 h. IGFBP-6 may have a functional role in the hyperthermic response as it induced chemotaxis of monocytes and T lymphocytes, but not of B lymphocytes. Thus, temperature regulates complex biological DC functions that most likely contribute to their ability to induce an efficient adaptive immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.18338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617388PMC
September 2017

Hematopoietic Stem Cell Transplantation: A Bioethical Lens.

Stem Cells Int 2017 27;2017:1286246. Epub 2017 Jun 27.

Institute of Legal Medicine, Department of Clinical and Experimental Medicine, University of Foggia, Ospedale 'Colonnello D'Avanzo', Viale Degli Aviatori 1, 71122 Foggia, Italy.

Hematopoietic stem cell transplantation (HSCT) is one of a range of therapeutic options available to patients suffering from various diseases. HSCT procedure involves important ethical and legal aspects that can occur at every phase of the procedure: the clinical choice of whether to perform the procedure, pretransplantation preparation regimens, donor selection, stem cell harvest procedure, transplantation phase, and short-term and long-term follow-up care. In this discussion paper, we outline the ethical issue-facing physicians involved in HSCT. Currently, HSCT is a widely accepted treatment for many life-threatening diseases. It thus represents a real therapeutic hope for many patients. It does, however, carry a burden of possible morbidity and mortality. Consequently, there are substantial information and communication issues involved in the consent process for HSCT. In the final decision, the judgements of different parties, such as patients, family members, and healthcare professionals, intersect and overlap and this is particularly true when the patient is a minor. Finally, HSCT is a very expensive procedure. The social and economic concerns of HSCT are discussed within the actual contextual framework of the dramatic increase in healthcare costs and inequalities in healthcare in relation to socioeconomic status, educational status, and ethnicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2017/1286246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504964PMC
June 2017

Donor Selection for Allogenic Hemopoietic Stem Cell Transplantation: Clinical and Ethical Considerations.

Stem Cells Int 2017 7;2017:5250790. Epub 2017 Jun 7.

Institute of Legal Medicine, Department of Clinical and Experimental Medicine, University of Foggia, Ospedale "Colonnello D'Avanzo", Viale Degli Aviatori, 1, 71122 Foggia, Italy.

Allogenic hematopoietic progenitor cell transplantation (allo-HSCT) is an established treatment for many diseases. Stem cells may be obtained from different sources: mobilized peripheral blood stem cells, bone marrow, and umbilical cord blood. The progress in transplantation procedures, the establishment of experienced transplant centres, and the creation of unrelated adult donor registries and cord blood banks gave those without an human leucocyte antigen- (HLA-) identical sibling donor the opportunity to find a donor and cord blood units worldwide. HSCT imposes operative cautions so that the entire donation/transplantation procedure is safe for both donors and recipients; it carries with it significant clinical, moral, and ethical concerns, mostly when donors are minors. The following points have been stressed: the donation should be excluded when excessive risks for the donor are reasonable, donors must receive an accurate information regarding eventual adverse events and health burden for the donors themselves, a valid consent is required, and the recipient's risks must be outweighed by the expected benefits. The issue of conflict of interest, when the same physician has the responsibility for both donor selection and recipient care, is highlighted as well as the need of an adequate insurance protection for all the parties involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2017/5250790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478865PMC
June 2017

Insulin-Like Growth Factor Binding Protein 6 in Rheumatoid Arthritis: A Possible Novel Chemotactic Factor?

Front Immunol 2017 18;8:554. Epub 2017 May 18.

Department of Medicine and Surgery, University of Foggia, Foggia, Italy.

Objectives: Immune cell migration from the bloodstream to target tissues is a hallmark of rheumatoid arthritis (RA) pathogenesis. The role of chemoattractants, mainly chemokines, and their possible targeting for therapeutic purposes have been under intense investigation over the last few years but the results were not as satisfactory as expected. The insulin-like growth factor binding protein 6 (IGFBP6), a direct inhibitor of insulin-like growth factor (IGF)-II, also exerts IGF-independent effects including tumor cell migration . We aimed to assess the expression of this protein in serum, synovial fluid, and synovial tissue (ST) of RA patients and to identify its possible chemotactic role in this disorder.

Methods: IGFBP6 was measured in RA patients and healthy donors (HD) sera by Luminex xMAP technology and in ST of RA patients and osteoarthritis (OA) controls by immunofluorescence. The identification of circulating IGFBP6 cells was evaluated by flow cytometry and an migration assay was arranged.

Results: We demonstrated that IGFBP6 is able to induce greater migration of RA as compared to HD and OA T lymphocytes and is overexpressed in serum and ST of RA patients. This chemotactic activity can be partially inhibited by dexamethasone.

Conclusion: Our findings suggest a pathogenic role of IGFBP6 in RA and support its possible targeting for therapeutic purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.00554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435743PMC
May 2017

Persistent Immune Stimulation Exacerbates Genetically Driven Myeloproliferative Disorders via Stromal Remodeling.

Cancer Res 2017 07 23;77(13):3685-3699. Epub 2017 May 23.

Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

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 () 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 -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 -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. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-17-1098DOI Listing
July 2017

PLAC1 immunization does not induce infertility in mice.

Immunotherapy 2017 05 29;9(6):481-486. Epub 2017 Mar 29.

Department of Experimental Medicine, University of Perugia, Perugia, Italy.

Aim: Placenta specific 1 (PLAC1) is a protein rarely expressed in normal cells, except it is important for placental development, with a possible role in the establishment of the mother-fetus interface. The gene is also highly active in a wide variety of cancers and therefore, immunization with PLAC1 peptides could possibly be part of future immunotherapeutic strategies. We investigated whether vaccination against PLAC1 could induce infertility.

Materials & Methods: We inoculated female mice with PLAC1 peptides, put them in mating, measured antibody response (ELISA assay) and checked, in immunohistochemistry, binding of the induced antibodies to the native antigen.

Results: We demonstrated that mice consistently develop antibody responses. We also demonstrated that female mice, after being inoculated with the PLAC1 peptide mix, do became pregnant and can give birth to normal infants.

Conclusion: PLAC1 antigens as a specific anti-cancer vaccine could induce anti-PLAC1 antibodies which do not necessarily cause infertility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/imt-2017-0019DOI Listing
May 2017

Cohesin complex is a major player on the stage of leukemogenesis.

Stem Cell Investig 2016 1;3:18. Epub 2016 Jun 1.

Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/sci.2016.05.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958060PMC
August 2016

Seasonal Variation in Skin Cancer Diagnosis.

Front Public Health 2016 28;4:78. Epub 2016 Apr 28.

Public Health Section, Department of Experimental Medicine, University of Perugia, Perugia, Italy; Umbrian Population Cancer Registry, Regional Government of Umbria, University of Perugia, Perugia, Italy.

Purpose: Seasonality of skin cancer is well known, and it is influenced by a number of variables, such as exposure and personal characteristics, but also health service factors. We investigated the variations in the diagnosis melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC) during the year.

Methods: We analyzed incident cases recorded in the Umbria Regional Cancer registry from 1994 to 2010 (1745 cases of MSC, 50% females, and 15,992 NMSC, 41% females). The Walter-Elwood test was used to assess seasonal effects. Relative risks were analyzed using negative binomial regression and splines.

Results: Seasonality of MSC and NMSC was similar. Incidence peaks were observed in weeks 8, 24, and 43 (February, July, and October) and troughs in weeks 16, 32, 52, and 1 (August and December). Both NMSC and MSC cancers showed most elevated risks in autumn. A seasonal effect was present for trunk (p < 0.001) and absent for face cancers (p = 0.3).

Conclusion: The observed pattern of diagnoses presumably depends on health service factors (e.g., organization of melanoma days, reduced access to care in August and during Christmas holidays) and personal factors (e.g., unclothing in the summer and delays in seeking care). High incidence rates in autumn could also in part depend on a late cancer progression effect of UV exposure. More efforts should be placed in order to guarantee uniform access to care through the year.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpubh.2016.00078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848301PMC
May 2016

Immunophenotypic and molecular features of 'cuplike' acute myeloid leukemias.

Eur J Haematol 2014 Feb;92(2):121-6

Department of Emergency - Section of Haematology, University of Bari, Bari, Italy.

Nuclear invaginations, also referred to as fishmouth or cuplike nuclei, have long been identified in microgranular APL, myelomonocytic and monocytic AMLs. More recently, this typical morphological feature has been associated with NPM1 and FLT3 mutations, as well as with the lack of CD34 and HLA-DR expression. In this study, we retrospectively analyzed the morphologic, immunophenotypic, cytogenetic, and molecular features of 68 patients with AML. A cuplike nuclear invagination was detected in more than 10% of blast cells in 15 (22%) cases. Our data show that a cuplike morphology is associated with FLT3-ITD positivity, as well as with the loss of CD34 and HLA-DR expression. The results were not significantly modified when a higher cutoff of cuplike cells was used. Our results are not sufficient to suggest that cuplike AML could represent a distinct subtype, but further investigations could yield a better characterization of this feature in patients with AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.12217DOI Listing
February 2014

Rapid long-lasting biochemical and radiological response to sorafenib in a case of advanced hepatocellular carcinoma.

Oncol Lett 2013 Mar 11;5(3):975-977. Epub 2013 Jan 11.

Units of Clinical Oncology, University of Foggia, Foggia I-71100, Italy.

The multikinase inhibitor sorafenib has demonstrated an overall survival benefit in phase III hepatocellular carcinoma (HCC) trials and has become the new standard of care for advanced stages of this disease. However, in clinical practice, the vast majority of patients obtain disease stabilization and occasionally tumor shrinkage. Furthermore, the appropriate timing of sorafenib therapy initiation, in order to maximize its clinical activity, remains under debate. We report a case of 4-year sorafenib treatment in a patient with an advanced hepatitis C virus (HCV)-related HCC with extensive infiltration of the inferior vena cava. Sorafenib treatment induced a rapid complete biochemical response and a long-term favorable outcome. Additionally, no major toxicities or detrimental effects on quality of life were observed. Thus, it is likely that a subgroup of human HCC may be highly sensitive to sorafenib; new molecular determinants are required to select those patients who may benefit from this therapy. Furthermore, a prompt initiation of treatment when the hepatic function is not compromised is a prerequisite for maximizing the clinical activity of sorafenib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ol.2013.1131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576208PMC
March 2013

Genome-wide computational approach for the prediction of duplications generating protein localization signals.

Comput Biol Med 2012 Nov 24;42(11):1091-7. Epub 2012 Sep 24.

DiSBeF, Department of Base Sciences and Fundamentals, University of Urbino, Urbino, Italy.

Investigating the possible generation of motifs accountable for aberrant protein dislocation subsequent to the rise of short tandem duplications is interesting, given the pathogenic potential of this mechanism, as demonstrated in diseases such adult myeloid leukemia (AML). In this paper we introduce a new computational method for predicting genomic points which, after hypothetical mutation events such as micro-duplications, might encode molecular patterns such as localization or export signals. The proposed framework allows to study motifs of unconstrained length defined as regular expressions at a genome-wide level, providing an in silico platform capable of analyzing the potential effect of duplications on abnormal cellular localization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiomed.2012.09.001DOI Listing
November 2012

Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype.

Blood 2011 Dec 19;118(23):6153-63. Epub 2011 Oct 19.

MLL Munich Leukemia Laboratory, Munich, Germany.

Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardio-dental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-07-365320DOI Listing
December 2011

BRAF mutations in hairy-cell leukemia.

N Engl J Med 2011 Jun 11;364(24):2305-15. Epub 2011 Jun 11.

Institute of Hematology, University of Perugia, Perugia, Italy.

Background: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure.

Methods: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL.

Results: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1014209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689585PMC
June 2011

Low dose intravenous bevacizumab for the treatment of anaemia in hereditary haemorrhagic telangiectasia.

Br J Haematol 2011 Feb 1;152(4):365. Epub 2010 Dec 1.

Unit of Geriatrics and Gerontology and Rare Diseases, Department of Internal Medicine and Public Health, University of Bari, Polyclinic, Bari, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2141.2010.08481.xDOI Listing
February 2011

Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity?

Blood 2011 Jan 28;117(4):1109-20. Epub 2010 Oct 28.

Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy.

After the discovery of NPM1-mutated acute myeloid leukemia (AML) in 2005 and its subsequent inclusion as a provisional entity in the 2008 World Health Organization classification of myeloid neoplasms, several controversial issues remained to be clarified. It was unclear whether the NPM1 mutation was a primary genetic lesion and whether additional chromosomal aberrations and multilineage dysplasia had any impact on the biologic and prognostic features of NPM1-mutated AML. Moreover, it was uncertain how to classify AML patients who were double-mutated for NPM1 and CEBPA. Recent studies have shown that: (1) the NPM1 mutant perturbs hemopoiesis in experimental models; (2) leukemic stem cells from NPM1-mutated AML patients carry the mutation; and (3) the NPM1 mutation is usually mutually exclusive of biallelic CEPBA mutations. Moreover, the biologic and clinical features of NPM1-mutated AML do not seem to be significantly influenced by concomitant chromosomal aberrations or multilineage dysplasia. Altogether, these pieces of evidence point to NPM1-mutated AML as a founder genetic event that defines a distinct leukemia entity accounting for approximately one-third of all AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2010-08-299990DOI Listing
January 2011

CD34+ cells from AML with mutated NPM1 harbor cytoplasmic mutated nucleophosmin and generate leukemia in immunocompromised mice.

Blood 2010 Nov 15;116(19):3907-22. Epub 2010 Jul 15.

Institute of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy.

Acute myeloid leukemia (AML) with mutated NPM1 shows distinctive biologic and clinical features, including absent/low CD34 expression, the significance of which remains unclear. Therefore, we analyzed CD34(+) cells from 41 NPM1-mutated AML. At flow cytometry, 31 of 41 samples contained less than 10% cells showing low intensity CD34 positivity and variable expression of CD38. Mutational analysis and/or Western blotting of purified CD34(+) cells from 17 patients revealed NPM1-mutated gene and/or protein in all. Immunohistochemistry of trephine bone marrow biopsies and/or flow cytometry proved CD34(+) leukemia cells from NPM1-mutated AML had aberrant nucleophosmin expression in cytoplasm. NPM1-mutated gene and/or protein was also confirmed in a CD34(+) subfraction exhibiting the phenotype (CD34(+)/CD38(-)/CD123(+)/CD33(+)/CD90(-)) of leukemic stem cells. When transplanted into immunocompromised mice, CD34(+) cells generated a leukemia recapitulating, both morphologically and immunohistochemically (aberrant cytoplasmic nucleophosmin, CD34 negativity), the original patient's disease. These results indicate that the CD34(+) fraction in NPM1-mutated AML belongs to the leukemic clone and contains NPM1-mutated cells exhibiting properties typical of leukemia-initiating cells. CD34(-) cells from few cases (2/15) also showed significant leukemia-initiating cell potential in immunocompromised mice. This study provides further evidence that NPM1 mutation is a founder genetic lesion and has potential implications for the cell-of-origin and targeted therapy of NPM1-mutated AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2009-08-238899DOI Listing
November 2010

Reduced percentage of natural killer cells associated with impaired cytokine network in the secretory endometrium of infertile women with polycystic ovary syndrome.

Fertil Steril 2010 Nov 16;94(6):2222-7, 2227.e1-3. Epub 2010 Mar 16.

Institute of Obstetrics and Gynecology, Department of Surgical Sciences, University of Foggia, Foggia, Italy.

Objective: To evaluate lymphocyte subset distribution in the secretory endometrium from infertile patients with polycystic ovary syndrome (PCOS), and the expression of the cytokines known to play a role in determining the endometrial lymphocyte pattern.

Design: Experimental clinical study.

Setting: Outpatient clinic in a university hospital.

Patient(s): Twenty-eight patients with PCOS (PCOS group) and 6 fertile patients (control group).

Intervention(s): On days 22-26 of a spontaneous cycle, subjects underwent endometrial biopsies.

Main Outcomes Measure(s): In 19 of 28 patients with PCOS and 6 controls with a late secretory endometrium, the percentage and phenotype of lymphocyte subsets were analyzed by flow cytometry. In the late secretory endometrium of 11 patients with PCOS and 3 controls, the expression of interleukins 15 and 18 and of chemokine ligand 10 was also analysed by polymerase chain reaction.

Result(s): In patients with PCOS the percentage of CD56+/CD16- and of CD56bright/CD16- cells was significantly lower (median [confidence interval]: 38% [31%-52.7%] vs. 63.7% [57.7%-69%] and 17.4% [8%-41.6%] vs. 52% [43%-60%], respectively), whereas the percentage of CD3+ was significantly higher (45% [33.3%-64%] vs. 26.1% [21%-32%]) as compared with controls. Accordingly, polymerase chain reaction analysis revealed a significantly lower expression of interleukins 15 and 18 and of chemokine ligand 10 in patients with PCOS than in controls.

Conclusion(s): Results demonstrated an abnormal percentage of endometrial lymphocyte subsets, associated with an impaired cytokine network in patients with PCOS. This could explain the poor reproductive potential in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fertnstert.2010.01.049DOI Listing
November 2010

Abnormal pattern of lymphocyte subpopulations in the endometrium of infertile women with chronic endometritis.

Am J Reprod Immunol 2009 May;61(5):322-9

Department of Surgical Sciences, Institute of Obstetrics and Gynecology, University of Foggia, viale Pinto, Foggia, Italy.

Problem: Endometrial lymphocytes play a critical role in endometrial receptivity. This study aimed at evaluating the variations induced by chronic endometritis (CE) on endometrial lymphocyte subsets. We compared the results in infertile women diagnosed with CE with those in unexplained infertile women without any sign of CE.

Method Of Study: Twenty-three women referring for unexplained infertility had hysteroscopy and endometrial biopsy in the follicular phase; in nine women, CE was diagnosed (group CE+), while in 14 it was not (group CE-). All patients in the late secretory phase of the subsequent cycle underwent endometrial biopsy. By flow cytometry, the percentage and phenotype of the endometrial lymphocyte subpopulations were analyzed.

Results: The secretory endometrium of patients with CE displayed significantly lower percentage of CD56(+) CD16(-) and of CD56(bright) CD16(-) cells (47.8% +/- 18.6 and 30.1% +/- 20.5 versus 79.5% +/- 3.9 and 67.3% +/- 8.1, respectively; P < 0.01) as compared with group CE(-), while the percentage of CD3(+) cells was significantly higher (25% +/- 12.2 versus 10.5 +/- 5; P < 0.01).

Conclusion: Infertile women with CE showed an abnormal percentage of endometrial lymphocyte subsets compared with unexplained infertile women suggesting that different mechanisms underlie the adverse pregnancy outcome of the two groups of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1600-0897.2009.00698.xDOI Listing
May 2009

A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1).

Haematologica 2008 Aug 4;93(8):1219-26. Epub 2008 Jul 4.

Institute of Hematology, University of Foggia, Foggia, Italy.

Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc(+) acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc(+) acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.13209DOI Listing
August 2008

Cytoplasmic mutated nucleophosmin is stable in primary leukemic cells and in a xenotransplant model of NPMc+ acute myeloid leukemia in SCID mice.

Haematologica 2008 May 26;93(5):775-9. Epub 2008 Mar 26.

Institute of Hematology, University of Perugia, Perugia, Italy.

We investigated the NPM1 mutation status or subcellular expression of NPM protein (nuclear vs. aberrant cytoplasmic) at diagnosis and relapse in 125 patients with acute myeloid leukemia from Italy and Germany. All 52 patients with acute myeloidleukemia carrying at diagnosis mutated or cytoplasmic NPM (NPMc(+) acute myeloid leukemia) retained this feature at relapse. Notably, cytoplasmic mutated NPM has now been retained for eight years in a xenotransplant model of NPMc(+) acute myeloid leukemia in immunodeficient mice. None of 73 acute myeloid leukemia patients carrying at diagnosis wild-type NPM1 gene or showing at immunohistochemistry nucleus-restricted expression of nucleophosmin (NPMc(-) acute myeloid leukemia), which is predictive of NPM1 gene in germline configuration, acquired cytoplasmic mutated NPM at relapse. This finding further confirms that NPMc(+) acute myeloid leukemia represents a primary event rather than a transformation stage of NPMc(-) acute myeloid leukemia. The stability of cytoplasmic mutated NPM in patients with acute myeloid leukemia, even at relapse in extramedullary sites, and in a xenotransplant model, suggest this event is crucial for leukemogenesis and represents the rationale for monitoring minimal residual disease and molecular targeted therapy in NPMc(+) acute myeloid leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.12225DOI Listing
May 2008

Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin.

Proc Natl Acad Sci U S A 2008 Mar 28;105(10):3945-50. Epub 2008 Feb 28.

Departments of Medicine and Molecular Virology and Human Genetics, Comprehensive Cancer Center, and College of Pharmacology, Ohio State University, Columbus, OH 43221, USA.

Acute myeloid leukemia (AML) carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ AML) accounts for about one-third of adult AML and shows distinct features, including a unique gene expression profile. MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nucleotides in length that have been linked to the development of cancer. Here, we investigated the role of miRNAs in the biology of NPMc+ AML. The miRNA expression was evaluated in 85 adult de novo AML patients characterized for subcellular localization/mutation status of NPM1 and FLT3 mutations using a custom microarray platform. Data were analyzed by using univariate t test within BRB tools. We identified a strong miRNA signature that distinguishes NPMc+ mutated (n = 55) from the cytoplasmic-negative (NPM1 unmutated) cases (n = 30) and includes the up-regulation of miR-10a, miR-10b, several let-7 and miR-29 family members. Many of the down-regulated miRNAs including miR-204 and miR-128a are predicted to target several HOX genes. Indeed, we confirmed that miR-204 targets HOXA10 and MEIS1, suggesting that the HOX up-regulation observed in NPMc+ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD+ samples were characterized by up-regulation of miR-155. Further experiments demonstrated that the up-regulation of miR-155 was independent from FLT3 signaling. Our results identify a unique miRNA signature associated with NPMc+ AML and provide evidence that support a role for miRNAs in the regulation of HOX genes in this leukemia subtype. Moreover, we found that miR-155 was strongly but independently associated with FLT3-ITD mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0800135105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268779PMC
March 2008

Born to be exported: COOH-terminal nuclear export signals of different strength ensure cytoplasmic accumulation of nucleophosmin leukemic mutants.

Cancer Res 2007 Jul;67(13):6230-7

Section of Hematology and Immunology, University of Perugia, Perugia, Italy.

Creation of a nuclear export signal (NES) motif and loss of tryptophans (W) 288 and 290 (or 290 only) at the COOH terminus of nucleophosmin (NPM) are both crucial for NPM aberrant cytoplasmic accumulation in acute myelogenous leukemia (AML) carrying NPM1 mutations. Hereby, we clarify how these COOH-terminal alterations functionally cooperate to delocalize NPM to the cytoplasm. Using a Rev(1.4)-based shuttling assay, we measured the nuclear export efficiency of six different COOH-terminal NES motifs identified in NPM mutants and found significant strength variability, the strongest NES motifs being associated with NPM mutants retaining W288. When artificially coupled with a weak NES, W288-retaining NPM mutants are not exported efficiently into cytoplasm because the force (W288) driving the mutants toward the nucleolus overwhelms the force (NES) exporting the mutants into cytoplasm. We then used this functional assay to study the physiologic NH(2)-terminal NES motifs of wild-type NPM and found that they are weak, which explains the prominent nucleolar localization of wild-type NPM. Thus, the opposing balance of forces (tryptophans and NES) seems to determine the subcellular localization of NPM. The fact that W288-retaining mutants always combine with the strongest NES reveals mutational selective pressure toward efficient export into cytoplasm, pointing to this event as critical for leukemogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-07-0273DOI Listing
July 2007