Stephanos Kyrkanides

Stony Brook University, Stony Brook, New York, United States

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Publications (69)196.31 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor cell survival consists of an intricate balance between cell growth and cell death pathways involving receptor tyrosine kinases (i.e. HER1-4, IGF-1R etc.), MDM2 and the tumor suppressor proteins PTEN and p53.We recently demonstrated that sEcad is a valid oncogenic target which is significantly increased in human clinical skin SCC samples, UV-induced mouse tumors and cells and promotes tumor cell proliferation, migration and invasion by interacting and activating with the HER-PI3K/Akt/mTOR and MAPK axis. In resected human SCC tumors, we reported enhanced sEcad-HER1, sEcad-HER2 and sEcad-IGF-1R, but not FL-Ecad-RTK interactions. Here, we demonstrate that a sEcad antibody against the ectodomain of E-cadherin suppressed SCC growth and increased tumor differentiation in orthotopic cutaneous SCC xenografts by inhibiting proliferation and inducing apoptosis. A similar anti-sEcad antibody-induced inhibition of proliferation and induction of cell death was evident in PAM212 cells in vitro. Mechanistically, anti-sEcad administration upregulated an array of cell death pathways (i.e. Bad, active caspase-3 and cleaved PARP) and inhibited IAPs (survivin, livin etc.), RTKs (HER1, HER2, p95HER2 and IGF-1R), MAPK and PI3K/mTOR pro-survival signaling. Interestingly, in anti-sEcad mAb treated tumors and PAM212 cells, this effect was associated with a profound increase in membrane, cytosolic and nuclear levels of PTEN, enhanced cytosolic p53 and a decrease in MDM2 levels. Overall, our studies suggest that an antibody-based therapy against sEcad may be a novel therapeutic platform for cutaneous SCCs by hampering key proto-oncogenes (RTKs, IAPs and MDM2) and activating potent tumor suppressor proteins (PTEN and p53) intricately linked to tumor growth and survival.
    Molecular Cancer Therapeutics 04/2014; · 5.60 Impact Factor
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    ABSTRACT: Objective Heightened levels of sEcad are found in the serum of cancer patients and correlates with an unfavorable prognosis and later-stages of disease. In this study, we explored whether sEcad is elevated in human OPSCC specimens and FaDu cells. Additionally, we investigated sEcad-human EGFR and sEcad-IGF1R interactions and performed a functional analysis of sEcad in OPSCC cancers. Materials and methodssEcad, EGFR and IGF-1R levels were examined in human OPSCC specimens and cells by immunoblotting. sEcad-EGFR and sEcad-IGF-1R interactions were examined by immunoprecipitation and immunoblot assays. Levels of sEcad on EGFR and IGF-1R pathway components were evaluated by IB. The effects of sEcad on OPSCC proliferation, migration and invasion were assessed using standard cellular assays. ResultsStatistical analysis demonstrated that sEcad levels were significantly higher in OPSCC primary tumors and cells compared to normal controls. IP studies indicated that sEcad associated with EGFR and IGF-1R, and addition of sEcad resulted in a statistically significant increase in downstream signaling. Finally, cell based assays demonstrated enhanced sEcad-induced proliferation, migration and invasion, which was blocked by EGFR and IGF-1R inhibitors. Conclusions These findings suggest that sEcad may play an important role in OPSCC oncogenicity via its interaction and activation of EGFR and IGF-1R.This article is protected by copyright. All rights reserved.
    Oral Diseases 03/2014; · 2.38 Impact Factor
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    ABSTRACT: Recent literature suggests that sEcad exerts pro-oncogenic effects, possibly acting as a ligand for the human epidermal growth factor family. Here we show that sEcad is a novel candidate protein for drug targeting since it is increased in human and mouse HER2-positive (HER2+) breast tumors, MMTV-PyMT bodily fluids and human cell culture systems. Mechanistically, we show that endogenous sEcad, and to a lesser extent membrane-bound E-cadherin, associates with HER1, HER2, and HER3 in human and MMTV-PyMT mouse HER2+ tumors and with HER1 in triple negative breast cancer (TNBC) specimens. Furthermore, addition of exogenous recombinant human E-cadherin/Fc chimeric protein (rhEcad/Fc; sEcad) to HER2+ MCF-7, SKBR3, and HER2-negative MDA-MB-231 TNBC cells, resulted in sEcad-HER receptor family interactions, activation of HER1-4 and downstream pro-survival signaling, including the MAPK-PI3K/Akt/mTOR pathways and IAP family members. Lastly, we demonstrate that sEcad exerts pro-oncogenic effects via HER signaling, and acts additively with the HER ligand EGF to promote HER2+ breast cancer proliferation and migration, as well as TNBC invasion. Because sEcad associates and activates many of the oncogenic pathways that tumors utilize for growth and survival and serum levels in patients correlates with clinical response, suggests that targeted therapy against sEcad in combination with other therapies may potentially offer a novel therapeutic strategy for the treatment of breast cancers. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 06/2013; · 4.27 Impact Factor
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    ABSTRACT: PURPOSE: Although targeted therapies against HER2 have been one of the most successful therapeutic strategies for breast cancer, patients eventually developed acquired resistance from compensatory upregulation of alternate HERs and MAPK-PI3K/Akt/mTOR signaling. As, we and others, have shown that the soluble ectodomain fragment of E-cadherin (sEcad) exerts pro-oncogenic effects via HER1/2-mediated binding and activation of downstream pro-survival pathways, we explored whether targeting this ectodomain (DECMA-1 mAb) was effective in the treatment of HER2-positive breast cancers. EXPERIMENTAL DESIGN: MMTV-PyMT transgenic mice and HER2+/E-cadherin-positive MCF-7 and BT474 Trastuzumab-resistant (TtzmR) cells were treated with the DECMA-1 mAb. Antitumor responses were assessed by BrdU incorporation, apoptosis and necrosis. The underlying intracellular pro-oncogenic pathways were explored using subcellular fractionation, immunoprecipitation, fluorescence microscopy and immunoblotting. RESULTS: Treatment with DECMA-1 mAb significantly delayed tumor onset and attenuated tumor burden in MMTV-PyMT mice by reducing tumor cell proliferation and inducing apoptosis without any detectable cytotoxicity to mice or end-organs. In vitro, treatment of MCF-7 and BT474 TtzmR cells reduced proliferation and induced cancer cell apoptosis. Importantly, this inhibition of breast tumorigenesis was due to concomitant down-regulation, via ubiquitin-mediated degradation through the lysosome and proteasome pathways, of all HER family members, components of downstream PI3K/Akt/mTOR pro-survival signaling and suppression of IAPs. CONCLUSIONS: Our results establish that the E-cadherin ectodomain-specific mAb DECMA-1 inhibits Ecad+/HER2+ breast cancers by hindering tumor growth and inducing apoptosis via down-regulation of key oncogenic pathways involved in Trastuzumab resistance, thereby establishing a novel therapeutic platform for the treatment of HER2+ breast cancers.
    Clinical Cancer Research 04/2013; · 7.84 Impact Factor
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    ABSTRACT: Neuroinflammation is an important component of Alzheimer's disease (AD) pathogenesis and has been implicated in neurodegeneration. Interleukin-1 (IL-1), a potent inflammatory cytokine in the CNS, is chronically upregulated in human AD and believed to serve as part of a vicious inflammatory cycle that drives AD pathology. To further understand the role of IL-1β in AD pathogenesis, we used an inducible model of sustained IL-1β overexpression (IL-1β(XAT)) developed in our laboratory. The triple transgenic mouse model of AD, which develops plaques and tangles later in its life cycle, was bred with IL-1β(XAT) mice, and effects of IL-1β overexpression on AD pathology were assessed in F1 progeny. After 1 and 3 months of transgene expression, we found robust increases in tau phosphorylation despite an ∼70-80% reduction in amyloid load and fourfold to sixfold increase in plaque-associated microglia, as well as evidence of greater microglial activation at the site of inflammation. We also found evidence of increased p38 mitogen-activated protein kinase and glycogen synthase kinase-3β activity, which are believed to contribute to tau phosphorylation. Thus, neuroinflammation regulates amyloid and tau pathology in opposing ways, suggesting that it provides a link between amyloid accumulation and changes in tau and raising concerns about the use of immunomodulatory therapies in AD.
    Journal of Neuroscience 03/2013; 33(11):5053-64. · 6.91 Impact Factor
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    ABSTRACT: Neuroinflammation is an important component of Alzheimer's disease (AD) pathogenesis and has been implicated in neurodegeneration. Interleukin-1 (IL-1), a potent inflammatory cytokine in the CNS, is chronically upregulated in human AD and believed to serve as part of a vicious inflammatory cycle that drives AD pathology. To further understand the role of IL-1β in AD pathogenesis, we used an inducible model of sustained IL-1β overexpression (IL-1β(XAT)) developed in our laboratory. The triple transgenic mouse model of AD, which develops plaques and tangles later in its life cycle, was bred with IL-1β(XAT) mice, and effects of IL-1β overexpression on AD pathology were assessed in F1 progeny. After 1 and 3 months of transgene expression, we found robust increases in tau phosphorylation despite an ∼70-80% reduction in amyloid load and fourfold to sixfold increase in plaque-associated microglia, as well as evidence of greater microglial activation at the site of inflammation. We also found evidence of increased p38 mitogen-activated protein kinase and glycogen synthase kinase-3β activity, which are believed to contribute to tau phosphorylation. Thus, neuroinflammation regulates amyloid and tau pathology in opposing ways, suggesting that it provides a link between amyloid accumulation and changes in tau and raising concerns about the use of immunomodulatory therapies in AD
    Journal of Neuroscience 03/2013; 33(11):5053-64. · 6.91 Impact Factor
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    ABSTRACT: E-cadherin, a cell-cell adhesion glycoprotein, is frequently downregulated with tumorigenic progression. The extracellular domain of E-cadherin is cleaved by proteases to generate a soluble ectodomain fragment, termed sEcad, which is elevated in the urine or serum of cancer patients. In this study, we explored the functional role of sEcad in the progression of skin squamous cell carcinomas (SCCs). We found that full-length E-cadherin expression was decreased and sEcad increased in human clinical tumor samples as well as in ultraviolet (UV)-induced SCCs in mice. Interestingly, sEcad associated with members of the human epidermal growth factor receptor (HER) and insulin-like growth factor-1 (IGF-1R) family of receptors in human and UV-induced mouse tumors. Moreover, in both E-cadherin-positive (E-cadherin(+)) and -negative (E-cadherin(-)) cells in vitro, sEcad activated downstream mitogen-activated protein (MAP) kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling and enhanced tumor growth, motility and invasion, the latter via activation of matrix metalloproteinase-2 (MMP-2) and MMP-9. To this end, HER, PI3K or MEK inhibitors suppressed sEcad's tumorigenic effects, including proliferation, migration and invasion. Taken together, our data suggest that sEcad contributes to skin carcinogenesis via association with the HER/IGF-1R-family of receptors and subsequent activation of the MAPK and PI3K/Akt/mTOR pathways, thereby implicating sEcad as a putative therapeutic target in cutaneous SCCs.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.563.
    Oncogene 01/2013; · 8.56 Impact Factor
  • H Huang, G Shank, L Ma, Rh Tallents, S Kyrkanides
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    ABSTRACT: OBJECTIVE: The goal of this study was to investigate changes in nerve growth factor (NGF) and its high-affinity receptor-tropomyosin receptor kinase A (TrkA) expression in the TMJ after intra-articular inflammation. MATERIALS AND METHODS: We employed the Col1-IL1β(XAT) inducible model of joint inflammation. Changes in NGF and TrkA expression were evaluated by immunohistochemistry. The function of NGF on cell differentiation was assessed in vitro employing the ATDC5 chondrocyte cell line. RESULTS: NGF expression was observed in articular chondrocytes only after TMJ inflammation, whereas TrkA expression was detected in articular chondrocytes under both naïve as well as inflamed conditions. The potential effect of NGF on articular chondrocytes was studied on the ATDC5 cell line, whereby NGF decelerated the maturation rate of this chondrogenic cell line, presumably by arresting cell differentiation at the prehypertrophic stage of chondrocyte maturation. CONCLUSIONS: NGF-TrkA signaling in the TMJ provides potentially a means of protection against the development of osteoarthritis by decelerating chondrocyte differentiation. This discovery may lead to the development of novel therapies for osteoarthritis of the TMJ and other joints.
    Oral Diseases 11/2012; · 2.38 Impact Factor
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    ABSTRACT: This study evaluated whether GM2 ganglioside storage is necessary for neurodegeneration and neuroinflammation by performing β-hexosaminidase rescue experiments in neurons of HexB-/- mice. We developed a novel mouse model, whereby the expression of the human HEXB gene was targeted to neurons of HexB-/- mice by the Thy1 promoter. Despite β-hexosaminidase restoration in neurons was sufficient in rescuing HexB-/- mice from GM2 neuronal storage and neurodegeneration, brain inflammation persisted, including the presence of large numbers of reactive microglia/macrophages due to persisting GM2 presence in this cell type. In conclusion, our results suggest that neuroinflammation is not sufficient to elicit neurodegeneration as long as neuronal function is restored.
    Journal of Neuroinflammation 08/2012; 9:186. · 4.35 Impact Factor
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    ABSTRACT: Neuroinflammation is a local tissue response to injurious stimuli in the central nervous system (CNS) and is characterized by glial reactivity, induction of cytokines and chemokines, and vascular permeability. The cytokine interleukin (IL)-1β is rapidly induced following CNS insult, and is chronically expressed in neurodegenerative disorders such as Alzheimer’s disease (AD). We recently developed a novel method of sustained IL-1β production in the brain to study the link between IL-1β and AD pathogenesis. Utilizing this model, we have previously demonstrated reduction of plaque size and frequency accompanied by a robust neuroinflammatory response. These observations were limited to a single early time point in the course of AD plaque deposition and did not investigate other neurodegenerative endpoints. To extend these observations to other stages of disease progression and evaluate additional pathologic markers, we investigated the effects of age and duration of IL-1β overexpression in the APPswe/PS-1dE9 AD model on a congenic C57BL/6 background. We now report that IL1β overexpression leads to decreased 6E10 immunopositive plaque pathology regardless of age or duration. We also investigated whether IL-1β overexpression led to neuronal apoptosis or cholinergic axonal degeneration in the context of this AD model. Although we could demonstrate apoptosis of infiltrating inflammatory cells, we found no evidence for IL-1 associated apoptosis of neurons or cholinergic axon degeneration even after 5months of chronic neuroinflammation. Together, these observations point to a neuroprotective role for IL-1β in AD neuropathogenesis. KeywordsInterleukin-1–Alzheimer’s disease–Microglia–Chronic neuroinflammation
    Journal of Neuroimmune Pharmacology 01/2012; 7(1):156-164. · 3.80 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease in vivo. We employed the inducible Col1-IL1βXAT mouse model of osteoarthritis, in which induction of osteoarthritis in the knees and temporomandibular joints resulted in astrocyte and microglial activation in the brain, accompanied by upregulation of inflammation-related gene expression. The biological significance of the link between peripheral and brain inflammation was explored in the APP/PS1 mouse model of Alzheimer's disease (AD) whereby osteoarthritis resulted in neuroinflammation as well as exacerbation and acceleration of AD pathology. Induction of osteoarthritis exacerbated and accelerated the development of neuroinflammation, as assessed by glial cell activation and quantification of inflammation-related mRNAs, as well as Aβ pathology, assessed by the number and size of amyloid plaques, in the APP/PS1; Col1-IL1βXAT compound transgenic mouse. This work supports a model by which peripheral inflammation triggers the development of neuroinflammation and subsequently the induction of AD pathology. Better understanding of the link between peripheral localized inflammation, whether in the form of osteoarthritis, atherosclerosis or other conditions, and brain inflammation, may prove critical to our understanding of the pathophysiology of disorders such as Alzheimer's, Parkinson's and other neurodegenerative diseases.
    Journal of Neuroinflammation 09/2011; 8:112. · 4.35 Impact Factor
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    ABSTRACT: The functional matrix theory was first introduced in the orthodontic literature by Melvin Moss half century ago. Since its original introduction, several attempts have been made to test the validity of this theory with mixed results. In this paper, we present evidence generated using transgenic mice to test the role of neuronal function in craniofacial development. Our data confirmed previous observations that midface retrusion accompanied neuronal dysfunction in the HexB−/− mouse model of Sandhoff disease. Importantly, restoration of neuronal function after targeted expression of a therapeutic gene selectively in the neurons of HexB−/− mice resulted in normalization of midface development in this mouse model. Histological analysis of the cranial base revealed that abnormal development of the synchondroses underlies the attendant midface retrusion in this model: Neuronal dysfunction led to the absence of hypertrophic chondrocytes in the synchondroses, whereas restoration of neuronal function resulted in normalization of the cranial base development. Taken together, our studies suggest that neuronal function is critical for normal midface development, underscoring the importance of the functional matrix theory as originally proposed by Melvin Moss.
    Orthodontic Waves 01/2011; 70(1):1-7.
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    ABSTRACT: Interleukin (IL)-1beta is a proinflammatory cytokine implicated in several neurodegenerative disorders. Downstream actions of IL-1beta include production of prostaglandin (PG) E(2) by increasing expression of cyclooxygenase (COX) enzymes and prostaglandin E synthase (PGES) isoforms. We recently developed a transgenic mouse carrying a dormant human IL-1beta eXcisional Activation Transgene (XAT) for conditional and chronic up-regulation of IL-1beta in selected brain regions. This model is characterized by regionally specific glial activation, immune cell recruitment, and induction of cytokines and chemokines. Here, we aimed to elucidate the effects of long-term IL-1beta expression on the PGE(2) synthetic pathway and to determine the effects of PGs on inflammation and memory in our model. As expected, PGE(2) levels were significantly elevated after IL-1beta up-regulation. Quantitative real-time PCR analysis indicated significant induction of mRNAs for COX-1 and membranous PGES-1, but not COX-2 or other PGES isoforms. Immunohistochemistry revealed elevation of COX-1 but no change in COX-2 following sustained IL-1beta production. Furthermore, pharmacological inhibition of COX-1 and use of COX-1 knockout mice abrogated IL-1beta-mediated PGE(2) increases. Although COX-1 deficient mice did not present a dramatically altered neuroinflammatory phenotype, they did exhibit improved contextual fear memory. This data suggests a unique role for COX-1 in mediating chronic neuroinflammatory effects through PGE(2) production.
    Journal of Neurochemistry 07/2010; 114(1):247-58. · 3.97 Impact Factor
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    ABSTRACT: Similarly to humans, healthy, wild-type mice develop osteoarthritis, including of the temporomandibular joint (TMJ), as a result of aging. Pro-inflammatory cytokines, such as IL-1beta, IL-6, and TNFalpha, are known to contribute to the development of osteoarthritis, whereas TGFbeta has been associated with articular regeneration. We hypothesized that a balance between IL-1beta and TGFbeta underlies the development of TMJ osteoarthritis, whereby IL-1beta signaling down-regulates TGFbeta expression as part of disease pathology. Our studies in wild-type mice, as well as the Col1-IL1beta(XAT) mouse model of osteoarthritis, demonstrated an inverse correlation between IL-1beta and TGFbeta expression in the TMJ. IL-1beta etiologically correlated with joint pathology, whereas TGFbeta expression associated with IL-1beta down-regulation and improvement of articular pathology. Better understanding of the underlying inflammatory processes during disease will potentially enable us to harness inflammation for orofacial tissue regeneration.
    Journal of dental research 07/2009; 88(6):557-62. · 3.46 Impact Factor
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    ABSTRACT: The trigeminal sensory system was evaluated for the retrograde transfer of gene therapy vectors into the CNS. The feline immunodeficiency viral vector, FIV(HEXB), encoding for the human HEXB gene, was injected intra-articularly in the temporomandibular joint of 12 week-old HexB(-/-) mice displaying clinical and histopathological signs of Sandhoff disease. This treatment regiment reduced GM(2) storage and ameliorated neuroinflammation in the brain of HexB(-/-) mice, as well as attenuated behavioral deficits. In conclusion, retrograde transfer along trigeminal sensory nerves may prove to be a valuable route of gene therapy administration for the treatment of lysosomal storage disorders and other neurodegenerative diseases.
    Journal of neuroimmunology 04/2009; 209(1-2):139-42. · 2.84 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2009; 5(4).
  • Molecular Genetics and Metabolism - MOL GENET METAB. 01/2009; 96(2).
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    ABSTRACT: Pain from arthritis has been associated with peripheral sensitization of primary sensory afferents and the development of inflammation at the dorsal horns. This study was undertaken to determine whether the role of spinal interleukin-1beta (IL-1beta) in central processing of pain is important in the development of arthritis. Col1-IL-1betaXAT mice and GFAP-IL-1betaXAT mice were injected with the feline immunodeficiency virus (FIV) (Cre) vector in the right and left temporomandibular joints (TMJs), or in the cisterna magna, respectively, to induce IL-1beta expression in the dorsal horns of the spinal horn. To inhibit intrathecal IL-1 receptor type I (IL-1RI) signaling, FIV(IL-1Ra) vector was injected into the cisterna magna of Col1-IL-1betaXAT mice. The effects of IL-1RI receptor inhibition in GFAP-IL-1betaXAT mice were studied in the GFAP-IL-1betaXAT-IL-1RI(-/-) compound mouse model. Neuroinflammatory, sensory, and behavioral changes were evaluated in conjunction with arthritic changes in the TMJ, assessed by histopathologic and immunohistochemical analyses. Induction of an osteoarthritis-like condition in the TMJ in the Col1-IL-1betaXAT mouse model resulted in up-regulation of murine IL-1beta at the dorsal horns. Moreover, intrathecal inhibition of IL-1RI in Col1-IL-1betaXAT mice with arthritis led to amelioration of joint pathology and attenuation of the attendant joint pain. Overexpression of spinal IL-1beta in the recently developed GFAP-IL-1betaXAT somatic mosaic model of neuroinflammation led to development of arthritis-like pathology accompanied by increased pain-like behavior. Our results indicate that joint pathology and pain are dependent on spinal IL-1beta, and suggest the presence of a bidirectional central nervous system-peripheral joints crosstalk that may contribute to the development, expansion, and exacerbation of arthritis.
    Arthritis & Rheumatology 11/2008; 58(10):3100-9. · 7.48 Impact Factor
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    ABSTRACT: Myeloid-derived immune cells, including microglia, macrophages and monocytes, have been previously implicated in neurodegeneration. We investigated the role of infiltrating peripheral blood mononuclear cells (PBMC) in neuroinflammation and neurodegeneration in the HexB-/- mouse model of Sandhoff disease. Ablation of the chemokine receptor CCR2 in the HexB-/- mouse resulted in significant inhibition of PBMC infiltration into the brain, decrease in TNFalpha and MHC-II mRNA abundance and retardation in clinical disease development. There was no change in the level of GM2 storage and pro-apoptotic activity or astrocyte activation in HexB-/-; Ccr2-/- double knockout mice, which eventually succumbed secondary to GM2 gangliosidosis.
    Journal of Neuroimmunology 10/2008; 203(1):50-7. · 3.03 Impact Factor
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    ABSTRACT: The etiology of midface retrusion remains largely unclear. We hypothesized that the cranial base synchondroses play a key role in the development of the craniofacial skeleton in the Sandhoff mouse model. We observed that developmental abnormalities of the cranial base synchondroses involving proliferative chondrocytes are important in craniofacial growth and development. Neonatal restitution of beta-hexosaminidase in mutant mice by gene therapy successfully ameliorated the attendant skeletal defects and restored craniofacial morphology in vivo, suggesting this as a critical temporal window in craniofacial development. Analysis of our data implicates parathyroid-related peptide (PTHrP) and cyclo-oxygenase-2 (COX-2) as possible factors underlying the development of the aforementioned skeletal defects. Hence, timely restitution of a genetic deficiency or, alternatively, the restoration of PTHrP or cyclo-oxygenase activity by the administration of PTH and/or non-steroidal anti-inflammatory drugs or COX-2 selective inhibitors to affected individuals may prove beneficial in the management of midface retrusion.
    Journal of Dental Research 11/2007; 86(10):956-61. · 3.83 Impact Factor

Publication Stats

1k Citations
196.31 Total Impact Points

Institutions

  • 2009–2014
    • Stony Brook University
      • Department of Emergency Medicine
      Stony Brook, New York, United States
    • Seoul National University
      • Dental Research Institute
      Seoul, Seoul, South Korea
  • 2010–2013
    • Stony Brook University Hospital
      Stony Brook, New York, United States
  • 1999–2010
    • University of Rochester
      • • Department of Neurobiology and Anatomy
      • • School of Medicine and Dentistry
      Rochester, NY, United States
  • 1999–2009
    • University Center Rochester
      Rochester, Minnesota, United States
  • 2006–2008
    • New York University College of Dentistry
      New York City, New York, United States