Veronica Papa

Bio: Veronica Papa is an academic researcher from University of Naples Federico II. The author has contributed to research in topics: Protein kinase B & PI3K/AKT/mTOR pathway. The author has an hindex of 15, co-authored 30 publications receiving 1241 citations. Previous affiliations of Veronica Papa include University of Cassino & University of Bologna.

MMP Activity in the Hybrid Layer Detected with in situ Zymography

Abstract: Dentinal proteases are believed to play an important role in the degradation of hybrid layers (HL). This study investigated the HL gelatinolytic activity by in situ zymography and functional enzyme activity assay. The hypotheses were that HLs created by an etch-and-rinse adhesive exhibit active gelatinolytic activity, and MMP-2 and -9 activities in dentin increase during adhesive procedures. Etched-dentin specimens were bonded with Adper Scotchbond 1XT and restored with composite. Adhesive/dentin interface slices were placed on microscope slides, covered with fluorescein-conjugated gelatin, and observed with a multi-photon confocal microscope after 24 hrs. Human dentin powder aliquots were prepared and assigned to the following treatments: A, untreated; B, etched with 10% phosphoric acid; or C, etched with 10% phosphoric acid and mixed with Scotchbond 1XT. The MMP-2 and -9 activities of extracts of dentin powder were measured with functional enzyme assays. Intense and continuous enzyme activity was detected at the bottom of the HL, while that activity was more irregular in the upper HL. Both acid-etching and subsequent adhesive application significantly increased MMP-2 and -9 activities (p < 0.05). The results demonstrate, for the first time, intrinsic MMP activity in the HL, and intense activation of matrix-bound MMP activity with both etching and adhesive application.

Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts

Abstract: A high incidence of relapses following induction chemotherapy is a major hindrance to patient survival in acute myelogenous leukemia (AML). There is strong evidence that activation of the phosphoinositide 3 kinase (PI3K)/Akt signaling network plays a significant role in rendering AML blasts drug resistant. An important mechanism underlying drug resistance is represented by overexpression of membrane drug transporters such as multidrug resistance-associated protein 1 (MRP1) or 170-kDa P-glycoprotein (P-gp). Here, we present evidence that MRP1, but not P-gp, expression is under the control of the PI3K/Akt axis in AML blasts. We observed a highly significant correlation between levels of phosphorylated Akt and MRP1 expression in AML cells. Furthermore, incubation of AML blasts with wortmannin, a PI3K pharmacological inhibitor, resulted in lower levels of phosphorylated Akt, downregulated MRP1 expression, and decreased Rhodamine 123 extrusion in an in vitro functional dye efflux assay. We also demonstrate that wortmannin-dependent PI3K/Akt inhibition upregulated p53 protein levels in most AML cases, and this correlated with diminished MRP1 expression and enhanced phosphorylation of murine double minute 2 (MDM2). Taken together, these data suggest that PI3K/Akt activation may lead to the development of chemoresistance in AML blasts through a mechanism involving a p53-dependent suppression of MRP1 expression.

Teaching anatomy in the XXI century: New aspects and pitfalls

Abstract: Anatomy has historically been a cornerstone in medical education regardless of nation, racial background, or medical school system. By learning gross anatomy, medical students get a first “impression” about the structure of the human body which is the basis for understanding pathologic and clinical problems. Although the importance of teaching anatomy to both undergraduate and postgraduate students remains undisputed, there is currently a relevant debate concerning methods of anatomy teaching. In the past century, dissection and lectures were its sole pedagogy worldwide. Recently, the time allocated for anatomy teaching was dramatically reduced to such an extent that some suggest that it has fallen below an adequate standard. Traditional anatomy education based on topographical structural anatomy taught in lectures and gross dissection classes has been replaced by a multiple range of study modules, including problem-based learning, plastic models or computer-assisted learning, and curricula integration. “Does the anatomical theatre still have a place in medical education?” And “what is the problem with anatomic specimens?” We endeavor to answer both of these questions and to contribute to the debate on the current situation in undergraduate and graduate anatomy education.

Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells

Abstract: The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myelogenous leukemia (AML). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine, on human AML cells. Perifosine is a synthetic alkylphospholipid, a new class of antitumor agents, which target plasma membrane and inhibit signal transduction networks. Perifosine was tested on THP-1 and MV 4-11 cell lines, as well as primary leukemia cells. Perifosine treatment induced cell death by apoptosis in AML cell lines. Perifosine caused Akt and ERK 1/2 dephosphorylation as well as caspase activation. In THP-1 cells, the proapoptotic effect of perifosine was partly dependent on the Fas/FasL system and c-jun-N-kinase activation. In MV 4-11 cells, perifosine downregulated phosphorylated Akt, but not phosphorylated FLT3. Moreover, perifosine reduced the clonogenic activity of AML, but not normal, CD34(+) cells, and markedly increased blast cell sensitivity to etoposide. Our findings indicate that perifosine, either alone or in combination with existing drugs, might be a promising therapeutic agent for the treatment of those AML cases characterized by upregulation of the PI3K-Akt survival pathway.

Synergistic Proapoptotic Activity of Recombinant TRAIL Plus the Akt Inhibitor Perifosine in Acute Myelogenous Leukemia Cells

Abstract: To potentiate the response of acute myelogenous leukemia (AML) cells to TNF-Related Apoptosis- Inducing Ligand (TRAIL) cytotoxicity we have examined the efficacy of a combination with perifosine a novel phosphatidylinositol 3-kinase (PI3K)/Akt signaling inhibitor. The rationale for using such a combination is that perifosine was recently described to increase TRAIL-R2 receptor expression and decrease the cellular FLICE-Inhibitory Protein (cFLIP) in human lung cancer cell lines. Perifosine and TRAIL both induced cell death by apoptosis in the THP-1 AML cell line which is characterized by constitutive PI3K/Akt activation but lacks functional p53. Perifosine at concentrations below IC50 dephosphorylated Akt and increased TRAIL-R2 levels as demonstrated by western blot RT-PCR and flow cytometric analysis. Perifosine also decreased the long isoform of cFLIP (cFLIP-L) and the X-linked Inhibitor of Apoptosis Protein (XIAP) expression. Perifosine nd TRAIL synergized to activate caspase-8 and induce apoptosis which was blocked by a caspase- 8 selective inhibitor. Upregulation of TRAIL-R2 expression was dependent on a protein kinase CI±/ c-Jun-NH2-kinase 2/c-Jun signaling pathway activated by perifosine through reactive oxygen species production. Perifosine synergized with TRAIL also in primary AML cells displaying constitutive activation of the Akt pathway by inducing apoptosis Akt dephosphorylation TRAIL-R2 pregulation cFLIP-L and XIAP downregulation and c-Jun phosphorylation. The combined treatment negatively affected the clonogenic activity of CD34+ cells from AML patients. In contrast CD34+ cells from healthy donors were resistant to perifosine and TRAIL treatment. Our findings suggest that the combination perifosine and TRAIL might offer a novel therapeutic strategy for AML. Originally published Cancer Research Vol. 68 No. 22 Nov 2008

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

Abstract: William H. Chappell 1 , Linda S. Steelman 1,2 , Jacquelyn M. Long 2 , Ruth C. Kempf 2 , Stephen L. Abrams 1 , Richard A. Franklin 1 , Jorg Basecke 3 , Franca Stivala 4 , Marco Donia 4 , Paolo Fagone 4 , Graziella Malaponte 4 , Maria C. Mazzarino 4 , Ferdinando Nicoletti 4 , Massimo Libra 4 , Danijela Maksimovic-Ivanic 5 , Sanja Mijatovic 5 , Giuseppe Montalto 6 , Melchiorre Cervello 7 , Piotr Laidler 8 , Michele Milella 9 , Agostino Tafuri 10 , Antonio Bonati 11 , Camilla Evangelisti 12 , Lucio Cocco 12 , Alberto M. Martelli 12,13 , and James A. McCubrey 1 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University 2 Department of Physics, Greenville, NC 27858 USA 3 Department of Medicine University of Gottingen, Gottingen, Germany 4 Department of Biomedical Sciences, University of Catania, Catania, Italy 5 Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia 6 Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 7 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy 8 Department of Medical Biochemistry Jagiellonian University Medical College, Krakow, Poland 9 Regina Elena Cancer Center, Via Elio Chianesi n.53, Rome 00144, Italy 10 University of Rome, La Sapienza, Department of Hematology-Oncology, Via Benevento 6, Rome 99161, Italy 11 University Hospital of Parma, Unit of Hematology and Bone-Marrow Transplantation, Via Gramsi n.14, Parma 43100, Italy 12 Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell’Apparato Locomotore, Universita di Bologna, Bologna, Italy 13 IGM-CNR, Sezione di Bologna, C/o IOR, Bologna, Italy Keywords: Targeted Therapy, Combination Therapy, Drug Resistance, Cancer Stem Cells, Aging, Senescence, Raf, Akt, PI3K, mTOR Received: February 25, 2011; Accepted: March 10, 2011; Published: March 11, 2011; Correspondence: James A. McCubrey, e-mail: // // Abstract The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.

The effectiveness of virtual and augmented reality in health sciences and medical anatomy.

Abstract: Although cadavers constitute the gold standard for teaching anatomy to medical and health science students, there are substantial financial, ethical, and supervisory constraints on their use. In addition, although anatomy remains one of the fundamental areas of medical education, universities have decreased the hours allocated to teaching gross anatomy in favor of applied clinical work. The release of virtual (VR) and augmented reality (AR) devices allows learning to occur through hands-on immersive experiences. The aim of this research was to assess whether learning structural anatomy utilizing VR or AR is as effective as tablet-based (TB) applications, and whether these modes allowed enhanced student learning, engagement and performance. Participants (n = 59) were randomly allocated to one of the three learning modes: VR, AR, or TB and completed a lesson on skull anatomy, after which they completed an anatomical knowledge assessment. Student perceptions of each learning mode and any adverse effects experienced were recorded. No significant differences were found between mean assessment scores in VR, AR, or TB. During the lessons however, VR participants were more likely to exhibit adverse effects such as headaches (25% in VR P < 0.05), dizziness (40% in VR, P < 0.001), or blurred vision (35% in VR, P < 0.01). Both VR and AR are as valuable for teaching anatomy as tablet devices, but also promote intrinsic benefits such as increased learner immersion and engagement. These outcomes show great promise for the effective use of virtual and augmented reality as means to supplement lesson content in anatomical education. Anat Sci Educ 10: 549-559. © 2017 American Association of Anatomists.

Multiple roles of phosphoinositide-specific phospholipase C isozymes.

Abstract: Phosphoinositide-specific phospholipase C is an effector molecule in the signal transduction process. It generates two second messengers, inositol-1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. Currently, thirteen mammal PLC isozymes have been identified, and they are divided into six groups: PLC-beta, -gamma, -delta, -epsilon, -zeta and -eta. Sequence analysis studies demonstrated that each isozyme has more than one alternative splicing variant. PLC isozymes contain the X and Y domains that are responsible for catalytic activity. Several other domains including the PH domain, the C2 domain and EF hand motifs are involved in various biological functions of PLC isozymes as signaling proteins. The distribution of PLC isozymes is tissue and organ specific. Recent studies on isolated cells and knockout mice depleted of PLC isozymes have revealed their distinct phenotypes. Given the specificity in distribution and cellular localization, it is clear that each PLC isozyme bears a unique function in the modulation of physiological responses. In this review, we discuss the structural organization, enzymatic properties and molecular diversity of PLC splicing variants and study functional and physiological roles of each isozyme.