Publications by authors named "Anna Maria Billi"

53 Publications

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia.

Int J Mol Sci 2021 Jan 15;22(2). Epub 2021 Jan 15.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy.

Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.
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http://dx.doi.org/10.3390/ijms22020827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830211PMC
January 2021

The whole body donation program at the university of Bologna: A report based on the experience of one of the oldest university in Western world.

Ann Anat 2021 Mar 17;234:151660. Epub 2020 Dec 17.

Department of Biomedical and Neuromotor Sciences, Human Anatomy Section, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.

Human body dissection is fundamental in medical education, as it allows future physicians to learn about the body's morphology in three dimensions, to recognize anatomical variations and to develop and increase the essential qualities of respect, compassion and empathy for patients. It is equally important in clinical training as it allows surgeons to improve their manual dexterity and practical skills and to test innovative surgical techniques and devices. In Italy prior to 2020, body acquisition and use for study and research purposes were regulated by a generic set of old directives and national decrees which dealt only marginally with these issues. However, in 2013, a whole body donation program was officially set up at the Institute of Human Anatomy of the University of Bologna. Completely free and voluntary informed consent has always been regarded as a core prerequisite and, since its inception, the program exclusively accepted bequeathed bodies. On February 10, 2020, a specific law governing the disposition of post mortem human body and tissues for study, training and scientific research purposes was definitively enacted. The present work traces the University of Bologna's experience leading to the whole body donation program and the brand new dissecting room. It describes the program of Bologna as an example of "good practice" in body donation, aimed at ensuring education and clinical training by means of both traditional gross anatomy and innovative technology. Moreover, it analyzes the results achieved in terms of increased donor enrollment and improved teaching/training quality and the strengths of this program in light of the provisions enshrined in the new law.
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http://dx.doi.org/10.1016/j.aanat.2020.151660DOI Listing
March 2021

Phospholipase C beta1 (PI-PLCbeta1)/Cyclin D3/protein kinase C (PKC) alpha signaling modulation during iron-induced oxidative stress in myelodysplastic syndromes (MDS).

FASEB J 2020 Nov 22;34(11):15400-15416. Epub 2020 Sep 22.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

MDS are characterized by anemia and transfusion requirements. Transfused patients frequently show iron overload that negatively affects hematopoiesis. Iron chelation therapy can be effective in these MDS cases, but the molecular consequences of this treatment need to be further investigated. That is why we studied the molecular features of iron effect and Deferasirox therapy on PI-PLCbeta1 inositide signaling, using hematopoietic cells and MDS samples. At baseline, MDS patients showing a positive response after iron chelation therapy displayed higher levels of PI-PLCbeta1/Cyclin D3/PKCalpha expression. During treatment, these responder patients, as well as hematopoietic cells treated with FeCl and Deferasirox, showed a specific reduction of PI-PLCbeta1/Cyclin D3/PKCalpha expression, indicating that this signaling pathway is targeted by Deferasirox. The treatment was also able to specifically decrease the production of ROS. This effect correlated with a reduction of IL-1A and IL-2, as well as Akt/mTOR phosphorylation. In contrast, cells exposed only to FeCl and cells from MDS patients refractory to Deferasirox showed a specific increase of ROS and PI-PLCbeta1/Cyclin D3/PKCalpha expression. All in all, our data show that PI-PLCbeta1 signaling is a target for iron-induced oxidative stress and suggest that baseline PI-PLCbeta1 quantification could predict iron chelation therapy response in MDS.
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http://dx.doi.org/10.1096/fj.202000933RRDOI Listing
November 2020

Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes.

Int J Mol Sci 2020 Apr 8;21(7). Epub 2020 Apr 8.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.

Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In several cancer types, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P] play significant roles in regulating survival, proliferation, invasion, and growth of cancer cells. Phosphoinositide-specific phospholipase C (PLC) catalyze the generation of the essential second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (InsP) by hydrolyzing PtdIns(4,5)P. DAG and InsP regulate Protein Kinase C (PKC) activation and the release of calcium ions (Ca) into the cytosol, respectively. This event leads to the control of several important biological processes implicated in cancer. PLCs have been extensively studied in cancer but their regulatory roles in the oncogenic process are not fully understood. This review aims to provide up-to-date knowledge on the involvement of PLCs in cancer. We focus specifically on PLCβ, PLCγ, PLCδ, and PLCε isoforms due to the numerous evidence of their involvement in various cancer types.
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http://dx.doi.org/10.3390/ijms21072581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177890PMC
April 2020

Phosphoinositide 3 Kinase Signaling in Human Stem Cells from Reprogramming to Differentiation: A Tale in Cytoplasmic and Nuclear Compartments.

Int J Mol Sci 2019 04 24;20(8). Epub 2019 Apr 24.

Department of Biomedical Sciences, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy.

Stem cells are undifferentiated cells that can give rise to several different cell types and can self-renew. Given their ability to differentiate into different lineages, stem cells retain huge therapeutic potential for regenerative medicine. Therefore, the understanding of the signaling pathways involved in stem cell pluripotency maintenance and differentiation has a paramount importance in order to understand these biological processes and to develop therapeutic strategies. In this review, we focus on phosphoinositide 3 kinase (PI3K) since its signaling pathway regulates many cellular processes, such as cell growth, proliferation, survival, and cellular transformation. Precisely, in human stem cells, the PI3K cascade is involved in different processes from pluripotency and induced pluripotent stem cell (iPSC) reprogramming to mesenchymal and oral mesenchymal differentiation, through different and interconnected mechanisms.
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http://dx.doi.org/10.3390/ijms20082026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514809PMC
April 2019

Anatomic Cartography of the Hypogastric Nerves and Surgical Insights for Autonomic Preservation during Radical Pelvic Procedures.

J Minim Invasive Gynecol 2019 Nov - Dec;26(7):1340-1345. Epub 2019 Jan 29.

Department of Obstetrics and Gynecology, Functional Pelvic Surgery and Neuropelveology, University of Toronto, Toronto, Ontario, Canada (Dr. Lemos); Department of Gynecology, Pelvic Neurodysfunction Unit, Federal University of São Paulo, São Paulo, Brazil. (Dr. Lemos).

Study Objective: To clarify the relationship of hypogastric nerves (HNs) with several pelvic anatomic landmarks and to assess any anatomic differences between the 2 sides of the pelvis, both in cadaveric and in vivo dissections.

Design: Prospective observational study.

Setting: An anatomic theater for cadaveric dissections and a university hospital for in vivo laparoscopy.

Patients: Five nulliparous female cadavers underwent laparotomic dissection; 10 nulliparous patients underwent laparoscopic surgery for rectosigmoid endometriosis without posterolateral parametrial infiltration.

Interventions: Measurements of the closest distance between HNs and ureters, the midsagittal plane, the midcervical plane, and uterosacral ligaments on both hemipelvises. A comparison of anatomic data of the 2 hemipelvises was conducted.

Measurements And Main Results: The right and left HNs were identified in all specimens, both on cadavers and in vivo dissections. A wide anatomic variability was reported. Regarding the differences between the 2 hemipelvises, we found that the right HN was significantly (p <.001) farther to the ureter (mean = 14.5 mm; range, 10-25 mm) than the left one (mean = 8.6 mm; range, 7-12 mm). The HN was closer to the midsagittal plane on the right side (mean = 14.6 mm; range, 12-17 mm) than on the left side (mean = 21.6 mm; range, 19-25 mm). The midcervical plane was found 2.7 mm (range, 2-4 mm) to the left of the midsagittal one. The right HN was found to be nonsignificantly closer to the midcervical plane and the uterosacral ligament on the right side than on the left side (p >.05).

Conclusions: Despite a wide anatomic variability of position and appearance, the HNs are reproducibly identifiable using an "interfascial" technique and considering the ureters and uterosacral ligaments as anatomic landmarks.
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http://dx.doi.org/10.1016/j.jmig.2019.01.010DOI Listing
May 2020

Phospholipase C-β1 interacts with cyclin E in adipose- derived stem cells osteogenic differentiation.

Adv Biol Regul 2019 01 5;71:1-9. Epub 2018 Nov 5.

Section of Human Anatomy, Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy. Electronic address:

Adipose-derived stem cells (ADSCs) are multipotent mesenchymal stem cells that have the ability to differentiate into several cell types, including chondrocytes, osteoblasts, adipocytes, and neural cells. Given their easy accessibility and abundance, they became an attractive source of mesenchymal stem cells, as well as candidates for developing new treatments for reconstructive medicine and tissue engineering. Our study identifies a new signaling pathway that promotes ADSCs osteogenic differentiation and links the lipid signaling enzyme phospholipase C (PLC)-β1 to the expression of the cell cycle protein cyclin E. During osteogenic differentiation, PLC-β1 expression varies concomitantly with cyclin E expression and the two proteins interact. These findings contribute to clarify the pathways involved in osteogenic differentiation and provide evidence to develop therapeutic strategies for bone regeneration.
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http://dx.doi.org/10.1016/j.jbior.2018.11.001DOI Listing
January 2019

Endoscopic endonasal approach to primitive Meckel's cave tumors: a clinical series.

Acta Neurochir (Wien) 2018 12 31;160(12):2349-2361. Epub 2018 Oct 31.

Department of Neurosurgery, DIBINEM, University of Bologna, Bologna, Italy.

Introduction: Recently, an alternative endoscopic endonasal approach to Meckel's cave (MC) tumors has been proposed. To date, few studies have evaluated the results of this route. The aim of our study was to evaluate long-term surgical and clinical outcome associated with this technique in a cohort of patients with intrinsic MC tumors.

Methods: All patients with MC tumors treated at out institution by endoscopic endonasal approach (EEA) between 2002 and 2016 were included. Patients underwent brain MRI, CT angiography, and neurological evaluation before surgery. Complications were considered based on the surgical records. All examinations were repeated after 3 and 12 months, then annually. The median follow-up was of 44.1 months (range 16-210).

Results: The series included 8 patients (4 F): 5 neuromas, 1 meningioma, 1 chondrosarcoma, and 1 epidermoid cyst. The median age at treatment was 54.5 years (range 21-70). Three tumors presented with a posterior fossa extension. Radical removal of the MC portion of the tumor was achieved in 7 out of 8 cases. Two patients developed a permanent and transitory deficit of the sixth cranial nerve, respectively. No tumor recurrence was observed at follow-up.

Conclusion: In this preliminary series, the EEA appeared an effective and safe approach to MC tumors. The technique could be advantageous to treat tumors located in the antero-medial aspects of MC displacing the trigeminal structures posteriorly and laterally. A favorable index of an adequate working space for this approach is represented by the ICA medialization, while tumor extension to the posterior fossa represents the main limitation to radical removal of this route.
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http://dx.doi.org/10.1007/s00701-018-3708-4DOI Listing
December 2018

Nuclear inositide signaling and cell cycle.

Adv Biol Regul 2018 01 23;67:1-6. Epub 2017 Oct 23.

Cellular Signalling Laboratory Department of Biomedical Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.

Phosphatidylinositols (PIs) are responsible for several signaling pathways related to many cellular functions, such as cell cycle regulation at different check-points, cell proliferation, cell differentiation, membrane trafficking and gene expression. PI metabolism is not only present at the cytoplasmic level, but also at the nuclear one, where different signaling pathways affect essential nuclear mechanisms in eukaryotic cells. In this review we focus on nuclear inositide signaling in relation to cell cycle regulation. Many evidences underline the pivotal role of nuclear inositide signaling in cell cycle regulation and cell proliferation associated to different strategic physiopathological mechanisms in several cell systems and diseases.
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http://dx.doi.org/10.1016/j.jbior.2017.10.008DOI Listing
January 2018

PLC-β1 and cell differentiation: An insight into myogenesis and osteogenesis.

Adv Biol Regul 2017 Jan 18;63:1-5. Epub 2016 Oct 18.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Phosphoinositide-phospholipase C-β1 (PLC-β1) plays a crucial role in the initiation of the genetic program responsible for muscle differentiation and osteogenesis. During myogenic differentiation of murine C2C12 myoblasts, PLC-β1 signaling pathway involves the Inositol Polyphosphate Multikinase (IPMK) and β-catenin as downstream effectors. By means of c-jun binding to cyclin D3 promoter, the activation of PLC-β1 pathway determines cyclin D3 accumulation. However, osteogenesis requires PLC-β1 expression and up-regulation but it does not affect cyclin D3 levels, suggesting that the two processes require the activation of different mediators.
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http://dx.doi.org/10.1016/j.jbior.2016.10.005DOI Listing
January 2017

IPMK and β-catenin mediate PLC-β1-dependent signaling in myogenic differentiation.

Oncotarget 2016 Dec;7(51):84118-84127

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

In previous studies, we have reported that phospholipase C (PLC)-β1 plays a crucial role in myogenic differentiation and we determined the importance of its catalytic activity for the initiation of this process. Here we define the effectors that take part to its signaling pathway. We show that the Inositol Polyphosphate Multikinase (IPMK) is able to promote myogenic differentiation since its overexpression determines the up-regulation of several myogenic markers. Moreover, we demonstrate that IPMK activates the same cyclin D3 promoter region targeted by PLC-β1 and that IPMK-induced promoter activation relies upon c-jun binding to the promoter, as we have shown previously for PLC-β1. Furthermore, our data shows that IPMK overexpression causes an increase in β-catenin translocation and accumulation to the nuclei of differentiating myoblasts resulting in higher MyoD activation. Finally, we describe that PLC-β1 overexpression determines too an increase in β-catenin translocation and that PLC-β1, IPMK and β-catenin are mediators of the same signaling pathway since their overexpression results in cyclin D3 and myosin heavy chain (MYH) induction.
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http://dx.doi.org/10.18632/oncotarget.11527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356648PMC
December 2016

Endoscopic endonasal anatomy of the ophthalmic artery in the optic canal.

Acta Neurochir (Wien) 2016 07 27;158(7):1343-50. Epub 2016 Apr 27.

Center of Surgery for Pituitary Tumors and Endoscopic Skull Base Surgery, Department of Neurosurgery, IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.

Background: The endoscopic endonasal opening of the optic canal has been recently proposed for tumors with medial invasion of this canal, such as tuberculum sellae meningiomas. Injury of the ophthalmic artery represents a dramatic risk during this maneuver. Therefore, the aim of this study was to analyze the endoscopic endonasal anatomy of the precanalicular and canalicular portion of this vessel, discussing its clinical implication.

Methods: The course of the ophthalmic artery was analyzed through five endoscopic endonasal dissections, and 40 nonpathological consecutive MRAs were reviewed.

Results: The ophthalmic artery arises from the intradural portion of the supraclinoid internal carotid artery, in 93 % of cases about 1.9 mm (range: 1-3) posterior to the falciform ligament. At the entrance into the optic canal, the ophthalmic artery is located infero-medially to the optic nerve in 13 % of cases. In 50 % of these cases the artery moves infero-laterally along its course, remaining in a medial position in the others. In cases with an non medial entrance of the ophthalmic artery, it runs infero-lateral to the optic nerve for its entire canalicular portion, with just one exception.

Conclusion: The endoscopic endonasal approach gives a direct, extensive and panoramic view of the course of the precanalicular and canalicular portion of the ophthalmic artery. Dedicated high-field neuroimaging studies are of paramount importance in preoperative planning to evaluate the anatomy of the ophthalmic artery, reducing the risk of jeopardizing the vessel, particularly for those uncommon cases with an infero-medial course of the artery.
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http://dx.doi.org/10.1007/s00701-016-2797-1DOI Listing
July 2016

Selective Activation of Nuclear PI-PLCbeta1 During Normal and Therapy-Related Differentiation.

Curr Pharm Des 2016 ;22(16):2345-8

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.

Nuclear phosphoinositide-phospholipase C (PI-PLC) beta1 plays a crucial role in the molecular steps that regulate cell proliferation and differentiation in several experimental models, such as myoblasts and hematopoietic cells, via interaction with other important molecular players. Indeed, PI-PLCbeta1 and its related molecules are definitely involved in hematopoiesis, and particularly in drug-induced myeloid or erythroid differentiation. Here, we review the role of nuclear PI-PLCbeta1 signalling in normal hematopoiesis, in pathogenesis and in drug-related induction of hematopoietic differentiation, with particular reference to the current therapy of Myelodysplastic Syndromes (MDS).
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http://dx.doi.org/10.2174/1381612822666160226132338DOI Listing
November 2017

Nuclear Phosphatidylinositol Signaling: Focus on Phosphatidylinositol Phosphate Kinases and Phospholipases C.

J Cell Physiol 2016 Aug 28;231(8):1645-55. Epub 2015 Dec 28.

Department of Biomedical Sciences, University of Bologna, Bologna, Italy.

Phosphatidylinositol (PI) metabolism represents the core of a network of signaling pathways which modulate many cellular functions including cell proliferation, cell differentiation, apoptosis, and membrane trafficking. An array of kinases, phosphatases, and lipases acts on PI creating an important number of second messengers involved in different cellular processes. Although, commonly, PI signaling was described to take place at the plasma membrane, many evidences indicated the existence of a PI cycle residing in the nuclear compartment of eukaryotic cells. The discovery of this mechanism shed new light on many nuclear functions, such as gene transcription, DNA modifications, and RNA expression. As these two PI cycles take place independently of one another, understanding how nuclear lipid signaling functions and modulates nuclear output is fundamental in the study of many cellular processes. J. Cell. Physiol. 231: 1645-1655, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcp.25273DOI Listing
August 2016

Inositide-dependent signaling pathways as new therapeutic targets in myelodysplastic syndromes.

Expert Opin Ther Targets 2016 Jun 17;20(6):677-87. Epub 2015 Dec 17.

a Cellular Signalling Laboratory, Institute of Human Anatomy, Department of Biomedical and Neuromotor Sciences , University of Bologna , Bologna , Italy.

Introduction: Nuclear inositide signaling pathways specifically regulate cell proliferation and differentiation. Interestingly, the modulation of nuclear inositides in hematological malignancies can differentially affect erythropoiesis or myelopoiesis. This is particularly important in patients with myelodysplastic syndromes (MDS), who show both defective erythroid and myeloid differentiation, as well as an increased risk of evolution into acute myeloid leukemia (AML).

Areas Covered: This review focuses on the structure and function of specific nuclear inositide enzymes, whose impairment could be linked with disease pathogenesis and cancer. The authors, stemming from literature and published data, discuss and describe the role of nuclear inositides, focusing on specific enzymes and demonstrating that targeting these molecules could be important to develop innovative therapeutic approaches, with particular reference to MDS treatment.

Expert Opinion: Demethylating therapy, alone or in combination with other drugs, is the most common and current therapy for MDS patients. Nuclear inositide signaling molecules have been demonstrated to be important in hematopoietic differentiation and are promising new targets for developing a personalized MDS therapy. Indeed, these enzymes can be ideal targets for drug design and their modulation can have several important downstream effects to regulate MDS pathogenesis and prevent MDS progression to AML.
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http://dx.doi.org/10.1517/14728222.2016.1125885DOI Listing
June 2016

An increased expression of PI-PLCβ1 is associated with myeloid differentiation and a longer response to azacitidine in myelodysplastic syndromes.

J Leukoc Biol 2015 Nov 14;98(5):769-80. Epub 2015 May 14.

*Cellular Signalling Laboratory, Institute of Human Anatomy, Dipartimento di Scienze Biomediche e NeuroMotorie, University of Bologna, Italy; Institute of Hematology "L. e A. Seràgnoli," S. Orsola-Malpighi University Hospital, Bologna, Italy; Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy; Unit of Blood Disease and Stem Cell Transplantation, University of Brescia, Italy; and Hematology Unit, Ospedale Civile di Piacenza, Italy

This study tested the hypothesis that PI-PLCβ1 is associated with myeloid differentiation and that its expression could be useful for predicting the response of MDS patients to azacitidine, as the clinical effect of epigenetic treatments is often detectable only after several cycles of therapy. To this end, PI-PLCβ1 was quantified on 70 MDS patients (IPSS risk: 13 Low, 20 Int-1, 31 Int-2, 6 High) at baseline and during the first 3 cycles of azacitidine. Results were then compared with the hematologic response, as assessed after the sixth cycle of azacitidine therapy. Overall, 60 patients completed 6 cycles of azacitidine, and for them, a clinical and molecular evaluation was possible: 37 of these patients (62%) showed a specific increase of PI-PLCβ1 mRNA within the first 3 cycles, which was associated with a longer duration of response and with an increased myeloid differentiation, as evidenced by PI-PLCγ2 induction and the recruitment of specific myeloid-associated transcription factors to the PI-PLCβ1 promoter during azacitidine response. Moreover, the increase of cyclin D3 gene expression throughout all of the therapy showed that PI-PLCβ1-dependent signaling is indeed activated in azacitidine responder patients. Taken together, our results show that PI-PLCβ1 quantification in MDS predicts the response to azacitidine and is associated with an increased myeloid differentiation.
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http://dx.doi.org/10.1189/jlb.2MA1114-541RDOI Listing
November 2015

Strategic Role of Nuclear Inositide Signalling in Myelodysplastic Syndromes Therapy.

Mini Rev Med Chem 2014 Oct 13. Epub 2014 Oct 13.

Cellular Signalling Laboratory, Institute of Human Anatomy, DIBINEM, University of Bologna, via Irnerio 48, 40126 Bologna, Italy..

Nuclear inositide signalling is implicated in normal and pathological cell proliferation and differentiation in several distinct models. Among the key molecules of nuclear inositide pathways, phosphoinositide-phospholipase (PI-PLC) C β1 is essential for regulating hematopoiesis, particularly along myeloid and erythroid lineage. Moreover, Akt activation is associated with protein synthesis, via mTOR pathway, and with erythroid induction, through PI-PLCγ1 activation. Myelodysplastic syndromes (MDS) are a series of heterogeneous diseases characterized by ineffective hemopoiesis, with a variable risk of evolution into acute myeloid leukemia (AML). Therapeutic approaches for MDS include demethylating agents, such as azacitidine, aiming at reducing cell proliferation, and erythropoietin, useful for sustaining a normal erythropoiesis. In the last few years, a role for nuclear inositide signalling as a therapeutic target in MDS has been disclosed, in that PI-PLCβ1 increase is associated with azacitidine responsiveness, even when this drug is used in combination with other agents, and Akt is specifically activated in MDS at higher risk of AML evolution. On the other hand, recent data demonstrated that inositide signalling can also be involved in erythroid therapy, given the inhibitory effect of erythropoietin on PI-PLCβ1 and the activation of Akt/PI-PLCγ1 pathway, following the administration of erythropoietin. Here, we review the strategic role of nuclear inositide signalling in MDS, in pathogenesis and therapy.
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October 2014

Hepato-gastric and spleno-mesenteric arterial trunks: anatomical variation report and review of literature.

Ital J Anat Embryol 2013 ;118(2):217-22

The celiac trunk is one of the main arteries arising from abdominal aorta and supplies blood to several abdominal organs. The typical branching in left gastric, splenic and common hepatic arteries undergoes relatively frequent variations. The authors report a rare variation of the celiac trunk in a Caucasian cadaver, with a hepato-gastric and a spleno-mesenteric arterial trunks which arise from the abdominal aorta in a routine dissection of a 98-year-old male cadaver. Detailed knowledge of this kind of variations is important to plan and perform surgery in this district.
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December 2014

Targeting the liver kinase B1/AMP-activated protein kinase pathway as a therapeutic strategy for hematological malignancies.

Expert Opin Ther Targets 2012 Jul 12;16(7):729-42. Epub 2012 Jun 12.

University of Bologna, Human Anatomy, via Irnerio 48, Bologna, 40126, Italy.

Introduction: Despite considerable advances, several hematological malignancies remain incurable with standard treatments. Therefore, there is a need for novel targeted and less toxic therapies, particularly for patients who develop resistance to traditional chemotherapeutic drugs. The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway has recently emerged as a tumor suppressor axis. A critical point is that the LKB1/AMPK network remains functional in a wide range of cancers and could be stimulated by drugs, such as N,N-dimethylimidodicarbonimidic diamide (metformin) or 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR).

Areas Covered: The literature data show that drugs activating LKB1/AMPK signaling induced cell cycle arrest, caspase-dependent apoptosis or autophagy in hematopoietic tumors. Moreover, metformin effectively inhibited mammalian target of rapamycin complex 1 (mTORC1)-controlled oncogenetic protein translation, which does not occur with allosteric mTORC1 inhibitors, such as rapamycin and its derivatives. Metformin was also capable of targeting leukemic stem cells, the most relevant target for leukemia eradication.

Expert Opinion: Data emerging from preclinical settings suggest that the LKB1/AMPK pathway is critically involved in regulating proliferation and survival of malignant hematopoietic cells. Thus, it is proposed that drugs activating the LKB1/AMPK axis may offer a novel and less toxic treatment option for some types of hematological malignancies.
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http://dx.doi.org/10.1517/14728222.2012.694869DOI Listing
July 2012

Nuclear PLCs affect insulin secretion by targeting PPARγ in pancreatic β cells.

FASEB J 2012 Jan 5;26(1):203-10. Epub 2011 Oct 5.

Department of Human Anatomy, University of Bologna, Bologna, Italy.

Type 2 diabetes is a heterogeneous disorder caused by concomitant impairment of insulin secretion by pancreatic β cells and of insulin action in peripheral target tissues. Studies with inhibitors and agonists established a role for PLC in the regulation of insulin secretion but did not distinguish between effects due to nuclear or cytoplasmic PLC signaling pathways that act in a distinct fashion. We report that in MIN6 β cells, PLCβ1 localized in both nucleus and cytoplasm, PLCδ4 in the nucleus, and PLCγ1 in the cytoplasm. By silencing each isoform, we observed that they all affected glucose-induced insulin release both at basal and high glucose concentrations. To elucidate the molecular basis of PLC regulation, we focused on peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor transcription factor that regulates genes critical to β-cell maintenance and functions. Silencing of PLCβ1 and PLCδ4 resulted in a decrease in the PPARγ mRNA level. By means of a PPARγ-promoter-luciferase assay, the decrease could be attributed to a PLC action on the PPARγ-promoter region. The effect was specifically observed on silencing of the nuclear and not the cytoplasmic PLC. These findings highlight a novel pathway by which nuclear PLCs affect insulin secretion and identify PPARγ as a novel molecular target of nuclear PLCs.
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http://dx.doi.org/10.1096/fj.11-186510DOI Listing
January 2012

The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling network and the control of normal myelopoiesis.

Histol Histopathol 2010 05;25(5):669-80

Department of Human Anatomy, University of Bologna, Bologna, Italy.

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation, differentiation, and survival under physiological conditions. Aberrant regulation of the PI3K/Akt/mTOR signal transduction network has been observed in a wide range of neoplasias, including malignant hematological disorders. This observation suggests that this signaling cascade could also play a critical role during normal hematopoiesis, a highly regulated process which results in the formation of all blood lineages. The development of blood cells comprises a complex series of events which are mainly regulated through the actions of cytokines, a large family of extracellular ligands than can stimulate many biological responses in a wide array of cell types. Several of these cytokines are known to activate the PI3K/Akt/mTOR signal transduction network and thus regulate proliferation, survival, and differentiation events during hematopoiesis. Moreover, hematopoiesis is strictly dependent on the correct functions of the bone marrow microenvironment. Here, we review the evidence which links the signals emanating from the PI3K/Akt/mTOR cascade with the functions of hematopoietic stem cells and the process of lineage commitment, which then gives rise to myeloid lineage-restricted cells. We then further highlight the key role played by the PI3K/Akt/mTOR network during erythropoiesis, megakaryocytopoiesis, and granulo-cytopoiesis/monocytopoiesis.
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http://dx.doi.org/10.14670/HH-25.669DOI Listing
May 2010

Identification of a functional nuclear export sequence in diacylglycerol kinase-zeta.

Cell Cycle 2010 Jan 29;9(2):384-8. Epub 2010 Jan 29.

Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Cell Signaling Laboratory, Università di Bologna, Bologna, Italy.

Diacylglycerol kinases (DGKs) are key regulators of diacylglycerol-dependent signaling pathways. Among the 10 DGK isoforms, DGK-zeta is the only nuclear form that contains a nuclear localization signal. Here, by site-directed mutagenesis, we showed that DGK-zeta also displays a functional independent nuclear export signal (NES) sequence between the amino acid residues 362-370. Indeed, the NES mutant forms of DGK-zeta accumulated in the nucleus to a much greater extent than wildtype DGK-zeta. Moreover, treatment with leptomycin B, an inhibitor of leucine-rich type NES, resulted in accumulation of both endogenous and ectopically expressed DGK-zeta in the nucleus, demonstrating that nuclear export of DGK-zeta is chromosome regional maintenance protein 1 (CRM1)-dependent. Previously, we reported that nuclear DGK-zeta is a negative regulator of cell cycle progression in C2C12 mouse myoblasts. In this paper, we documented that enhancement of DGK-zeta nuclear localization by NES sequence mutation, increases G(0)/G(1) block in C2C12 cells. Overall, our data demonstrate that DGK-zeta export from nucleus to cytoplasm is regulated by a leucine-rich NES through the exportin CRM1 and suggest that the nuclear localization of DGK-zeta could finely tune its function as a regulator of G(1)/S cell cycle transition.
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http://dx.doi.org/10.4161/cc.9.2.10469DOI Listing
January 2010

A role for PKCepsilon during C2C12 myogenic differentiation.

Cell Signal 2010 Apr 29;22(4):629-35. Epub 2009 Nov 29.

Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, 40126 Bologna, Italy.

In a previous report we have demonstrated that PLCgamma1 is involved in the differentiation process of C2C12 myoblasts, induced by insulin administration. In order to identify the downstream targets of PLCgamma1-dependent signalling, we have analyzed the expression of DAG-dependent PKC isoforms during muscle differentiation. We show that during myotube formation, there is a marked increase of PKCepsilon and eta expression, and that PKCepsilon is able to form a complex with PLCgamma1. The increase in PKCepsilon amount during myogenic differentiation is associated to an increase in PKCepsilon activity as well. Immunofluorescence analysis indicated that in growing C2C12 cells both PLCgamma1 and PKCepsilon localize in the cytoplasm with a distinct perinuclear accumulation. In insulin-treated cells, the expression of PLCgamma1 and PKCepsilon increases and the two proteins are still distributed mainly in the perinuclear region of the myotubes. We show that PLCgamma1-PKCepsilon complex co-localizes with protein 58K, a specific Golgi marker. Moreover, our results indicate that the Golgi-associated PKCepsilon form, i.e. PKCepsilon phosphorylated at Ser 729, is increased in differentiated myoblasts. Since it has been previously demonstrated that in C2C12 cells after insulin administration cyclin D3 levels could be modulated by PLCgamma1, we analyzed the effect on cyclin D3 expression of either PKCepsilon overexpression or silencing, in order to investigate whether PKCepsilon could also affect cyclin D3 expression. The results showed that either a modification of PKCepsilon expression or a change in its catalytic activity determines a variation of cyclin D3 levels and muscle differentiation in terms of myogenin expression. These data support a role for PKCepsilon in regulating insulin inositide-dependent PLCgamma1 signalling in skeletal muscle differentiation.
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http://dx.doi.org/10.1016/j.cellsig.2009.11.017DOI Listing
April 2010

Inositide signaling in the nucleus: from physiology to pathology.

Adv Enzyme Regul 2010 4;50(1):2-11. Epub 2009 Nov 4.

Cellular Signaling Laboratory Department of Anatomical Sciences, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.

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http://dx.doi.org/10.1016/j.advenzreg.2009.10.007DOI Listing
August 2010

Nuclear inositides: PI-PLC signaling in cell growth, differentiation and pathology.

Adv Enzyme Regul 2009 31;49(1):2-10. Epub 2008 Dec 31.

Cellular Signaling Laboratory Department of Anatomical Sciences, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1016/j.advenzreg.2008.12.001DOI Listing
September 2009

Involvement of nuclear PLCbeta1 in lamin B1 phosphorylation and G2/M cell cycle progression.

FASEB J 2009 Mar 21;23(3):957-66. Epub 2008 Nov 21.

Cellular Signaling Laboratory, Department of Human Anatomical Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.

Inositide-specific phospholipase Cbeta1 (PLCbeta1) signaling in cell proliferation has been investigated thoroughly in the G(1) cell cycle phase. However, little is known about its involvement in G(2)/M progression. We used murine erythroleukemia cells to investigate the role of PLCbeta1 in G(2)/M cell cycle progression and screened a number of candidate intermediate players, particularly mitogen-activated protein kinase (MAPK) and protein kinase C (PKC), which can, potentially, transduce serum mitogenic stimulus and induce lamin B1 phosphorylation, leading to G(2)/M progression. We report that PLCbeta1 colocalizes and physically interacts with lamin B1. Studies of the effects of inhibitors and selective si-RNA mediated silencing showed a role of JNK, PKCalpha, PKCbetaI, and the beta1 isoform of PI-PLC in cell accumulation in G(2)/M [as observed by fluorescence-activated cell sorter (FACS)]. To shed light on the mechanism, we considered that the final signaling target was lamin B1 phosphorylation. When JNK, PKCalpha, or PLCbeta1 were silenced, lamin B1 exhibited a lower extent of phosphorylation, as compared to control. The salient features to emerge from these studies are a common pathway in which JNK is likely to represent a link between mitogenic stimulus and activation of PLCbeta1, and, foremost, the finding that the PLCbeta1-mediated pathway represents a functional nuclear inositide signaling in the G(2)/M transition.
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http://dx.doi.org/10.1096/fj.08-121244DOI Listing
March 2009

Inositide signaling: Nuclear targets and involvement in myelodysplastic syndromes.

Adv Enzyme Regul 2008 17;48:2-9. Epub 2008 Mar 17.

Cellular Signalling Laboratory, Department of Anatomical Sciences, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.

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http://dx.doi.org/10.1016/j.advenzreg.2007.11.013DOI Listing
December 2008

Nuclear phospholipase C beta1 and cellular differentiation.

Front Biosci 2008 Jan 1;13:2452-63. Epub 2008 Jan 1.

Cellular Signaling Laboratory, Department of Anatomical Sciences, University of Bologna, 40126 Bologna, Italy.

Phosphoinositides (PI) are the most extensively studied lipids involved in cell signaling pathways. The bulk of PI is found in membranes where they are substrates for enzymes, such as kinases, phosphatases and phospholipases, which respond to the activation by cell-surface receptors. The outcome of the majority of signaling pathways involving lipid second messengers results in nuclear responses finally driving the cell into differentiation, proliferation or apoptosis. Some of these pathways are well established, such as that of PI-specific phospholipase C (PI-PLC), which cleaves phosphatidylinositol-4,5-bisphosphate (PIP2) into the two second messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). Two independent cycles of PI are present inside the cell. One is localized at the plasma membrane, while the most recently discovered PI cycle is found inside the nuclear compartment. The regulation of the nuclear PI pool is totally independent from the plasma membrane counterpart, suggesting that the nucleus constitutes a functionally distinct compartment of inositol lipids metabolism. In this report we will focus on the signal transduction-related metabolism of nuclear PI and review the most convincing evidence that the PI cycle is involved in differentiation programs in several cell systems.
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http://dx.doi.org/10.2741/2858DOI Listing
January 2008

Intranuclear 3'-phosphoinositide metabolism and apoptosis protection in PC12 cells.

Acta Biomed 2007 ;78 Suppl 1:113-9

Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia Umana, Cell Signaling Laboratory, Università di Bologna, Bologna, Italy.

Lipid second messengers, particularly those derived from the polyphosphoinositide metabolism, play a pivotal role in multiple cell signaling networks. Phosphoinositide 3-kinase (PI3K) generates specific 3'-phosphorylated inositol lipids that have been implicated in a multitude of cell functions. One of the best characterized targets of PI3K lipid products is the serine/threonine protein kinase Akt (protein kinase B). Recent findings have implicated the PI3K/Akt pathway in cancer progression because it stimulates cell proliferation and suppresses apoptosis. Evidence accumulated over the past 15 years has highlighted the presence of an autonomous nuclear inositol lipid cycle, and strongly suggests that lipid molecules are important components of signaling networks operating within the nucleus. PI3K, its lipid products, and Akt have also been identified at the nuclear level. In this review, we shall summarize the most updated findings about these molecules in relationship with suppression of apoptotic stimuli in PC12 cells.
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June 2007