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Luis Del Valle, MD

Associate Professor, Neuroscience

Associate Professor, Neurovirology

Associate Professor, Pathology and Laboratory Medicine

Location: Room 755 MERB

Telephone:  215-707-4998

Fax:  215-707-4888

Email: lvalle@temple.edu

Department of Neuroscience

Center for Neurovirology

Department of Pathology and Laboratory Medicine

MD, Universidad Nacional Autónoma de México, 1990

 

Specialist, Pathology, Hospital General de México, 1994

 

Postdoctoral Fellowship, Neuropathology - 1995

Thomas Jefferson University

Philadelphia, PA

 

Postdoctoral Fellowship, Neurovirology - 1999

Drexel (MCP Hahnemann) School of Medicine

Philadelphia, PA

 

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Understanding the physio-pathology of viral-induced tumors in the brain and other tissues by using combined molecular and histological techniques. Investigating the role of HIV-1 regulatory proteins in the development of CNS injury, and the mechanisms by which certain viruses, JCV in particular, deregulate apoptotic pathways in order to complete their replication cycles.

Research Summary

Due to their high mortality, poor prognosis, surgical complications and poor quality of life after surgery, brain tumors constitute a pernicious group among neoplastic diseases. Approximately 2.5% of all cancer deaths in the United States are due to brain tumors. With the exception of few inherited neoplastic syndromes, the etiology of brain tumors remains largely unknown. In recent years, however, several reports suggest the association of viruses, especially of the polyomavirus family with different types of human brain tumors. Belonging to this family is JC virus, a small (38-40 nm in diameter) double stranded, circular DNA virus. JCV can cause tumors when intra-cerebrally inoculated into rodents, and non-human primates. Tumorigenecity of JCV is most likely induced by the viral early gene product T-antigen, as demonstrated by the occurrence of a variety of neuroectodermal tumors, including medulloblastomas, in transgenic animals containing and expressing JCV T-antigen. The mechanism of oncogenesis involves the binding and inactivation of tumor suppressor proteins, most notably p53 and pRb.

We have performed PCR amplification using JCV specific primers in a large number of human brain tumors, including medulloblastomas, pilocytic astrocytomas, diffuse fibrillary astrocytomas, anaplastic gliomas, glioblastoma multiforme, oligodendrogliomas, gliomatosis cerebri, gliosarcomas, ependymomas and primary CNS lymphomas and we have found JCV DNA sequences in approximately 85% of the samples. Furthermore, immunohistochemical detection of viral proteins, including T-antigen and Agnoprotein was found in approximately 45% of the cases.

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS, result of the productive infection of oligodendrocytes by the opportunistic polyomavirus JCV. This disease, once considered rare, is more frequently seen since the AIDS pandemic. Apoptosis is a host defense mechanism to dispose of damaged cells, however certain viruses have the ability to de-regulate apoptotic pathways to complete their life cycles. One such pathway involves Survivin, a member of the inhibitor of apoptosis family, which is abundantly expressed during development in proliferating tissues, but should be absent in normal, terminally differentiated cells. Immunohistochemical studies in our lab have demonstrated the presence of Survivin in JCV infected cells of PML cases, oligodendrocytes and astrocytes in particular, while normal glial cells in unaffected areas of the same cases remained negative. Survivin up-regulation was corroborated in oligodendroglial and astrocytic cultures infected with JCV. Cell cycle analysis and DNA laddering demonstrated a significantly lower number of cells undergoing apoptosis upon JCV infection compared with non-infected cultures; siRNA inhibition of Survivin resulted in a dramatic increase in apoptotic cells in JCV infected cultures.

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10878711. Del Valle L, Croul S, Morgello S, Amini S, Rappaport J, Khalili K, Detection of HIV-1 Tat and JCV capsid protein, VP1, in AIDS brain with progressive multifocal leukoencephalopathy. J Neurovirol 6:3 (221-228) 2000 Jun

11117551. Del Valle L, Azizi SA, Krynska B, Enam S, Croul SE, Khalili K, Reactivation of human neurotropic JC virus expressing oncogenic protein in a recurrent glioblastoma multiforme. Ann Neurol 48:6 (932-936) 2000 Dec

11358858. Del Valle L, Gordon J, Assimakopoulou M, Enam S, Geddes JF, Varakis JN, Katsetos CD, Croul S, Khalili K, Detection of JC virus DNA sequences and expression of the viral regulatory protein T-antigen in tumors of the central nervous system. Cancer Res 61:10 (4287-4293) 2001 May 15

11854388. Del Valle L, Gordon J, Enam S, Delbue S, Croul S, Abraham S, Radhakrishnan S, Assimakopoulou M, Katsetos CD, Khalili K, Expression of human neurotropic polyomavirus JCV late gene product agnoprotein in human medulloblastoma. J Natl Cancer Inst 94:4 (267-273) 2002 Feb 20

11914404. Del Valle L, Delbue S, Gordon J, Enam S, Croul S, Ferrante P, Khalili K, Expression of JC virus T-antigen in a patient with MS and glioblastoma multiforme. Neurology 58:6 (895-900) 2002 Mar 26

12060623. Del Valle L, Enam S, Lassak A, Wang JY, Croul S, Khalili K, Reiss K, Insulin-like growth factor I receptor activity in human medulloblastomas. Clin Cancer Res 8:6 (1822-1830) 2002 Jun

14987161. Enam S, Sweet TM, Amini S, Khalili K, Del Valle L, Evidence for involvement of transforming growth factor beta1 signaling pathway in activation of JC virus in human immunodeficiency virus 1-associated progressive multifocal leukoencephalopathy. Arch Pathol Lab Med 128:3 (282-291) 2004 Mar

15016869. Del Valle L, Enam S, Lara C, Miklossy J, Khalili K, Gordon J, Primary central nervous system lymphoma expressing the human neurotropic polyomavirus, JC virus, genome. J Virol 78:7 (3462-3469) 2004 Apr

15630684. Del Valle L, White MK, Enam S, Oviedo SP, Bromer MQ, Thomas RM, Parkman HP, Khalili K, Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma. Cancer 103:3 (516-527) 2005 Feb 1

16146764. Del Valle L, Piña-Oviedo S, HIV disorders of the brain: pathology and pathogenesis. Front Biosci 11 (718-732) 2006 Jan 1

17392168. Piña-Oviedo S, Urbanska K, Radhakrishnan S, Sweet T, Reiss K, Khalili K, Del Valle L, Effects of JC virus infection on anti-apoptotic protein survivin in progressive multifocal leukoencephalopathy. Am J Pathol 170:4 (1291-1304) 2007 Apr

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Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

19834489. Gualco E, Urbanska K, Perez-Liz G, Sweet T, Peruzzi F, Reiss K, Del Valle L, IGF-IR-dependent expression of Survivin is required for T-antigen-mediated protection from apoptosis and proliferation of neural progenitors. Cell Death Differ :()2009 Oct 16

19747512. Romagnoli L, Wollebo HS, Deshmane SL, Mukerjee R, Del Valle L, Safak M, Khalili K, White MK, Modulation of JC virus transcription by C/EBPbeta. Virus Res 146:1-2(97-106)2009 Dec

19360424. Piña-Oviedo S, Khalili K, Del Valle L, Hypoxia inducible factor-1 alpha activation of the JCV promoter: role in the pathogenesis of progressive multifocal leukoencephalopathy. Acta Neuropathol 118:2(235-47)2009 Aug

19335536. Piña-Oviedo S, Del Valle L, Baquera-Heredia J, Ortiz-Hidalgo C, Immunohistochemical characterization of Renaut bodies in superficial digital nerves: further evidence supporting their perineurial cell origin. J Peripher Nerv Syst 14:1(22-6)2009 Mar

19273072. Gualco E, Wang JY, Del Valle L, Urbanska K, Peruzzi F, Khalili K, Amini S, Reiss K, IGF-IR in neuroprotection and brain tumors. Front Biosci 14:(352-75)2009 Jan 1

19204000. Deshmane SL, Mukerjee R, Fan S, Del Valle L, Michiels C, Sweet T, Rom I, Khalili K, Rappaport J, Amini S, Sawaya BE, Activation of the oxidative stress pathway by HIV-1 Vpr leads to induction of hypoxia-inducible factor 1alpha expression. J Biol Chem 284:17(11364-73)2009 Apr 24

19172383. Pattillo CB, Venegas B, Donelson FJ, Del Valle L, Knight LC, Chong PL, Kiani MF, Radiation-guided targeting of combretastatin encapsulated immunoliposomes to mammary tumors. Pharm Res 26:5(1093-100)2009 May

19117011. Urbanska K, Pannizzo P, Lassak A, Gualco E, Surmacz E, Croul S, Del Valle L, Khalili K, Reiss K, Estrogen receptor beta-mediated nuclear interaction between IRS-1 and Rad51 inhibits homologous recombination directed DNA repair in medulloblastoma. J Cell Physiol 219:2(392-401)2009 May

19074980. Brown MC, Staniszewska I, Lazarovici P, Tuszynski GP, Del Valle L, Marcinkiewicz C, Regulatory effect of nerve growth factor in alpha9beta1 integrin-dependent progression of glioblastoma. Neuro Oncol 10:6(968-80)2008 Dec

18786633. Del Valle L, Schwartzman RJ, Alexander G, Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain Behav Immun 23:1(85-91)2009 Jan

18780968. Darbinian N, Cui J, Basile A, Del Valle L, Otte J, Miklossy J, Sawaya BE, Amini S, Khalili K, Gordon J, Negative regulation of AbetaPP gene expression by pur-alpha. J Alzheimers Dis 15:1(71-82)2008 Sep

18719392. Mukerjee R, Deshmane SL, Fan S, Del Valle L, White MK, Khalili K, Amini S, Sawaya BE, Involvement of the p53 and p73 transcription factors in neuroAIDS. Cell Cycle 7:17(2682-90)2008 Sep 1

18712720. Brown MC, Staniszewska I, Del Valle L, Tuszynski GP, Marcinkiewicz C, Angiostatic activity of obtustatin as alpha1beta1 integrin inhibitor in experimental melanoma growth. Int J Cancer 123:9(2195-203)2008 Nov 1

18688812. Perez-Liz G, Del Valle L, Gentilella A, Croul S, Khalili K, Detection of JC virus DNA fragments but not proteins in normal brain tissue. Ann Neurol 64:4(379-87)2008 Oct

18676357. Brown MC, Staniszewska I, Lazarovici P, Tuszynski GP, Del Valle L, Marcinkiewicz C, Regulatory effect of nerve growth factor in {alpha}9{beta}1 integrin-dependent progression of glioblastoma. Neuro Oncol :()2008 Aug 8

18648329. Del Valle L, White MK, Khalili K, Potential mechanisms of the human polyomavirus JC in neural oncogenesis. J Neuropathol Exp Neurol 67:8(729-40)2008 Aug

18546270. Urbanska K, Pannizzo P, Grabacka M, Croul S, Del Valle L, Khalili K, Reiss K, Activation of PPARalpha inhibits IGF-I-mediated growth and survival responses in medulloblastoma cell lines. Int J Cancer 123:5(1015-24)2008 Sep 1

18381601. Eletto D, Russo G, Passiatore G, Del Valle L, Giordano A, Khalili K, Gualco E, Peruzzi F, Inhibition of SNAP25 expression by HIV-1 Tat involves the activity of mir-128a. J Cell Physiol 216:3(764-70)2008 Sep

18353421. Romagnoli L, Sariyer IK, Tung J, Feliciano M, Sawaya BE, Del Valle L, Ferrante P, Khalili K, Safak M, White MK, Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter. Virology 375:2(331-41)2008 Jun 5

18207252. Kremlev SG, Gaurnier-Hausser AL, Del Valle L, Perez-Liz G, Dimitrov S, Tuszynski G, Angiocidin promotes pro-inflammatory cytokine production and antigen presentation in multiple sclerosis. J Neuroimmunol 194:1-2(132-42)2008 Feb

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Postdoctoral Fellows:

Georgina Perez-Liz, MD

Sergio Piña-Oviedo, MD

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