Peter Pytel

University of Illinois at Chicago, Chicago, Illinois, United States

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Publications (58)254.6 Total impact

  • Brain Pathology 03/2015; 25(2):231-2. · 4.35 Impact Factor
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    ABSTRACT: NF-κB is a major regulator of age-dependent gene expression and the p50/NF-κB1 subunit is an integral modulator of NF-κB signaling. Here, we examined Nfkb1-/- mice to investigate the relationship between this subunit and aging. Although Nfkb1-/- mice appear similar to littermates at six months of age, by 12 months they have a higher incidence of several observable age-related phenotypes. In addition, aged Nfkb1-/- animals have increased kyphosis, decreased cortical bone, increased brain GFAP staining and a decrease in overall lifespan compared to Nfkb1+/+. In vitro, serially passaged primary Nfkb1-/- MEFs have more senescent cells than comparable Nfkb1+/+ MEFs. Also, Nfkb1-/- MEFs have greater amounts of phospho-H2AX foci and lower levels of spontaneous apoptosis than Nfkb1+/+, findings that are mirrored in the brains of Nfkb1-/- animals compared to Nfkb1+/+. Finally, in wildtype animals a substantial decrease in p50 DNA binding is seen in aged tissue compared to young. Together, these data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence. Moreover, loss of p50 DNA binding is a prominent feature of aged mice relative to young. These findings support the strong link between the NF-κB pathway and mammalian aging.
    Aging 11/2014; 6(11):931-43. · 4.89 Impact Factor
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    ABSTRACT: The slow-channel congenital myasthenic syndrome (SCS) is an inherited neurodegenerative disease that caused mutations in the acetylcholine receptor (AChR) affecting neuromuscular transmission. Leaky AChRs lead to Ca(2+) overload and degeneration of the neuromuscular junction (NMJ) attributed to activation of cysteine proteases and apoptotic changes of synaptic nuclei. Here we use transgenic mouse models expressing two different mutations found in SCS to demonstrate that inhibition of prolonged opening of mutant AChRs using fluoxetine not only improves motor performance and neuromuscular transmission but also prevents Ca(2+) overload, the activation of cysteine proteases, calpain, caspase-3 and 9 at endplates, and as a consequence, reduces subsynaptic DNA damage at endplates, suggesting a long term benefit to therapy. These studies suggest that prolonged treatment of SCS patients with open ion channel blockers that preferentially block mutant AChRs is neuroprotective. Copyright © 2014 Elsevier Inc. All rights reserved.
    Experimental Neurology 10/2014; · 4.62 Impact Factor
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    ABSTRACT: -Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy.
    Circulation Cardiovascular Genetics 09/2014; · 6.73 Impact Factor
  • International Journal of Surgical Pathology 06/2014; · 0.96 Impact Factor
  • Peter Pytel
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    ABSTRACT: The diagnosis of an inflammatory myopathy is often established based on basic histologic studies. Additional immunohistochemical studies are sometimes required to support the diagnosis and the classification of inflammatory myopathies. Staining for major histocompatibility complex 1 (MHC1) often shows increased sarcolemmal labeling in inflammatory myopathies. Endomysial capillary staining C5b-9 (membrane attack complex) is a feature that is reported as frequently associated with dermatomyositis. Immunohistochemical staining for C4d is widely used for various applications including the assessment of antibody-mediated rejection after solid organ transplantation. In the context of dermatomyositis, C4d staining has been described in skin biopsies but not in muscle biopsies. A total of 32 muscle biopsy specimens were examined. The hematoxylin and eosin-stained slides were reviewed, and immunohistochemical studies for MHC1, C5b-9, and C4d were conducted. The staining observed for C5b-9 and C4d was compared. Overall, the staining pattern for C4d mirrored the one observed for C5b-9 in the examined muscle biopsy specimens. There was high and statistically significant (P<0.0001) correlation between the staining seen with these 2 antibodies. Both antibodies labeled the cytoplasm of degenerating necrotic myofibers. In addition, both antibodies showed distinct endomysial capillary labeling in a subset of dermatomyositis. Areas with perifascicular atrophy often exhibited the most prominent vascular labeling for C4d and C5b-9. In conclusion, C4d and C5b-9 show similar expression patterns in muscle biopsies of patients with inflammatory myopathies and both highlight the presence of vascular labeling associated with dermatomyositis. C4d antibodies are widely used and may offer an alternative for C5b-9 staining.
    Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 06/2014; 22(9). · 2.06 Impact Factor
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    ABSTRACT: Microarray-based molecular signatures have not been widely integrated into neuroblastoma diagnostic classification systems due to the complexities of the assay and requirement for high-quality RNA. New digital technologies that accurately quantify gene expression using RNA isolated from formalin-fixed paraffin embedded (FFPE) tissues are now available. In this study, we describe the first use of a high-throughput digital system to assay the expression of genes in an “ultra-high risk” microarray classifier in FFPE high-risk neuroblastoma tumors. Customized probes corresponding to the 42 genes in a published multi-gene neuroblastoma signature were hybridized to RNA isolated from 107 FFPE high-risk neuroblastoma samples using the NanoString nCounterTM Analysis System. For classification of each patient, the Pearson's correlation coefficient was calculated between the standardized nCounterTM data and the molecular signature from the microarray data. We demonstrate that the nCounterTM 42-gene panel sub-stratified the high-risk cohort into two subsets with statistically significantly different overall survival (p=0.0027) and event-free survival (p=0.028). In contrast, none of the established prognostic risk markers (age, stage, tumor histology, MYCN status, and ploidy) were significantly associated with survival. We conclude that the nCounterTM System can reproducibly quantify expression levels of signature genes in FFPE tumor samples. Validation of this microarray signature in our high-risk patient cohort using a completely different technology emphasizes the prognostic relevance of this classifier. Prospective studies testing the prognostic value of molecular signatures in high-risk neuroblastoma patients using FFPE tumor samples and the nCounterTM System are warranted.
    Molecular oncology 05/2014; · 6.70 Impact Factor
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    ABSTRACT: EHD proteins have been implicated in intracellular trafficking, especially endocytic recycling, where they mediate receptor and lipid recycling back to the plasma membrane. Additionally, EHDs help regulate cytoskeletal reorganization and induce tubule formation. It was previously shown that EHD proteins bind directly to the C2 domains in myoferlin, a protein that regulates myoblast fusion. Loss of myoferlin impairs normal myoblast fusion leading to smaller muscles in vivo but the intracellular pathways perturbed by loss of myoferlin function are not well known. We now characterized muscle development in EHD1-null mice. EHD1-null myoblasts display defective receptor recycling and mislocalization of key muscle proteins, including caveolin-3 and Fer1L5, a related ferlin protein homologous to myoferlin. Additionally, EHD1-null myoblast fusion is reduced. We found that loss of EHD1 leads to smaller muscles and myofibers in vivo. In wildtype skeletal muscle EHD1 localizes to the transverse tubule (T-tubule), and loss of EHD1 results in overgrowth of T-tubules with excess vesicle accumulation in skeletal muscle. We provide evidence that tubule formation in myoblasts relies on a functional EHD1 ATPase domain. Moreover, we extended our studies to show EHD1 regulates BIN1 induced tubule formation. These data, taken together and with the known interaction between EHD and ferlin proteins, suggests that the EHD proteins coordinate growth and development likely through mediating vesicle recycling and the ability to reorganize the cytoskeleton.
    Developmental Biology 01/2014; · 3.64 Impact Factor
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    ABSTRACT: Dysferlin (DYSF) is a membrane-associated protein implicated in muscular dystrophy and vesicle movement and function in muscles. The precise role of dysferlin has been debated, partly because of the mild phenotype in dysferlin-null mice. We bred Dysf mice to mice lacking myoferlin (MKO) to generate mice lacking both myoferlin and dysferlin (FER). FER animals displayed progressive muscle damage with myofiber necrosis, internalized nuclei, and, at older ages, chronic remodeling and increasing creatine kinase levels. These changes were most prominent in proximal limb and trunk muscles and were more severe than in Dysf mice. Consistently, FER animals had reduced ad libitum activity. Ultrastructural studies uncovered progressive dilation of the sarcoplasmic reticulum and ectopic and misaligned transverse tubules in FER skeletal muscle. FER muscle, and Dysf- and MKO-null muscle, exuded lipid, and serum glycerol levels were elevated in FER and Dysf mice. Glycerol injection into muscle is known to induce myopathy, and glycerol exposure promotes detachment of transverse tubules from the sarcoplasmic reticulum. Dysf, MKO, and FER muscles were highly susceptible to glycerol exposure in vitro, demonstrating a dysfunctional sarcotubule system, and in vivo glycerol exposure induced severe muscular dystrophy, especially in FER muscle. Together, these findings demonstrate the importance of dysferlin and myoferlin for transverse tubule function and in the genesis of muscular dystrophy.
    American Journal Of Pathology 10/2013; · 4.60 Impact Factor
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    ABSTRACT: The slow-channel syndrome (SCS) is a congenital myasthenic disorder caused by point mutations in subunits of skeletal muscle acetylcholine receptor (AChR) leading to Ca(2+) overload and degeneration of the postsynaptic membrane, nuclei, and mitochondria of the neuromuscular junction (NMJ). In both SCS muscle biopsies and in transgenic mouse models for SCS (mSCS), the endplate regions are shrunken, and there is evidence of DNA damage in the subsynaptic region. Activated caspases-9, -3, and -7 are intensely co-localized at the NMJ, and the Ca(2+)-activated protease, calpain, and the atypical cyclin-dependent kinase, Cdk5, are over-activated in mSCS. Thus, the true mediator(s) of the disease process are not clear. Here, we demonstrate that selective inhibition of effector caspases, caspase-3 and -7, or initiator caspase, caspase-9, in limb muscle in vivo by localized expression of recombinant inhibitor proteins dramatically decreases subsynaptic DNA damage, increases endplate area and improves ultrastructural abnormalities in SCS transgenic mice. Calpain and Cdk5 are not affected by this treatment. On the other hand inhibition of Cdk5 by expression of a dominant negative form of Cdk5 has no effect on the degeneration. Together with previous studies these results indicate that, focal activation of caspase activity at the NMJ is the principal pathological process responsible for the synaptic apoptosis in the SCS. Thus, treatments that reduce muscle caspase activity are likely to be of benefit for SCS patients.
    Human Molecular Genetics 08/2013; · 6.68 Impact Factor
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    ABSTRACT: Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP14 inhibition and alteration of the cell cycle, we used an RNAi technique. Genetic knockdown of MMP14 in U87 and U251 glioma cells induced G2/M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP14 in clinical samples and in vitro models through downregulation of microRNA374. In vivo genetic knockdown of MMP14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma-bearing mice. Moreover, the combination of MMP14 silencing with TMZ and XRT significantly improved the survival of glioma-bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy. Glioblastoma remains an incurable form of brain cancer. In this manuscript, we show that inhibition of MMP14 can potentiate the efficacy of current standard of care which includes chemo- and radiotherapy.
    Cancer Medicine 08/2013; 2(4):457-67.
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    ABSTRACT: A major obstacle to the management of malignant glioma is the inability to effectively deliver therapeutic agent to the tumor. In this study, we describe a polymeric nanoparticle vector that not only delivers viable therapeutic, but can also be tracked in vivo using MRI. Nanoparticles, produced by a non-emulsion technique, were fabricated to carry iron oxide within the shell and the chemotherapeutic agent, temozolomide (TMZ), as the payload. Nanoparticle properties were characterized and subsequently their endocytosis-mediated uptake by glioma cells demonstrated. Convection enhanced delivery (CED) can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. Infusion of nanoparticles does not result in observable animal toxicity relative to control. CED of TMZ bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control. In conclusion, the described nanoparticle vector represents a unique multifunctional platform that can be used for image-guided treatment of malignant glioma.
    Nanomedicine: nanotechnology, biology, and medicine 07/2013; · 6.93 Impact Factor
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    Neurobiology of Disease 07/2013; 55:36. · 5.20 Impact Factor
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    ABSTRACT: In the pediatric population, intracranial fusiform aneurysms have been associated with human immunodeficiency virus/acquired immunodeficiency syndrome and rarely with opportunistic infections related to other immunodeficiencies. The HIV virus and other infectious organisms have been implicated in the pathophysiology of these aneurysms. We present a child with T-cell immunodeficiency but no evidence of human immunodeficiency virus or opportunistic intracranial infections that developed progressive bilateral fusiform intracranial aneurysms. Our findings suggest a role of immunodeficiency or inflammation in the formation of some intracranial aneurysms.
    Pediatric Neurology 02/2013; 48(2):130-4. · 1.50 Impact Factor
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    ABSTRACT: About 50% of all malignant peripheral nerve sheath tumors (MPNSTs) arise as neurofibromatosis type 1 associated lesions. In those patients malignant peripheral nerve sheath tumors are thought to arise through malignant transformation of a preexisting plexiform neurofibroma. The molecular changes associated with this transformation are still poorly understood. We sought to test the hypothesis that dysregulation of expression of kinases contributes to this malignant transformation. We analyzed expression of all 519 kinase genes in the human genome using the nanostring nCounter system. Twelve cases of malignant peripheral nerve sheath tumor arising in a background of preexisting plexiform neurofibroma were included. Both components were separately sampled. Statistical analysis compared global changes in expression levels as well as changes observed in the pairwise comparison of samples taken from the same surgical specimen. Immunohistochemical studies were performed on tissue array slides to confirm expression of selected proteins. The expression pattern of kinase genes can separate malignant peripheral nerve sheath tumors and preexisting plexiform neurofibromas. The majority of kinase genes is downregulated rather than overexpressed with malignant transformation. The patterns of expression changes are complex without simple recurring alteration. Pathway analysis demonstrates that differentially expressed kinases are enriched for kinases involved in the direct regulation of mitosis, and several of these show increased expression in malignant peripheral nerve sheath tumors. Immunohistochemical studies for the mitotic regulators BUB1B, PBK and NEK2 confirm higher expression levels at the protein level. These results suggest that the malignant transformation of plexiform neurofibroma is associated with distinct changes in the expression of kinase genes. The patterns of these changes are complex and heterogeneous. There is no single unifying alteration. Kinases involved in mitotic regulation are particularly enriched in the pool of differentially expressed kinases. Some of these are overexpressed and are therefore possible targets for kinase inhibitors.Modern Pathology advance online publication, 1 February 2013; doi:10.1038/modpathol.2012.242.
    Modern Pathology 02/2013; · 6.36 Impact Factor
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    ABSTRACT: Antimuscle-specific kinase (anti-MuSK) myasthenia (AMM) differs from antiacetylcholine receptor myasthenia gravis in exhibiting more focal muscle involvement (neck, shoulder, facial, and bulbar muscles) with wasting of the involved, primarily axial, muscles. AMM is not associated with thymic hyperplasia and responds poorly to anticholinesterase treatment. Animal models of AMM have been induced in rabbits, mice, and rats by immunization with purified xenogeneic MuSK ectodomain, and by passive transfer of large quantities of purified serum IgG from AMM patients into mice. The models have confirmed the pathogenic role of the MuSK antibodies in AMM and have demonstrated the involvement of both the presynaptic and postsynaptic components of the neuromuscular junction. The observations in this human disease and its animal models demonstrate the role of MuSK not only in the formation of this synapse but also in its maintenance.
    Annals of the New York Academy of Sciences 12/2012; 1274(1):140-7. · 4.38 Impact Factor
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    ABSTRACT: Outcome for the vast majority of high-risk neuroblastoma patients with refractory or relapsed disease is dismal. We report two high-risk patients who remain progression-free for more than 113 and 18 months following the diagnosis of refractory/relapsed disease who were treated with surgery alone. Complete resolution of a refractory thoracic mass and relapsed liver nodules was observed in one patient. The refractory/relapsed disease in the second patient has remained stable. In both cases, the tumor showed histologic evidence of neuroblastoma maturation. These cases demonstrate that refractory/relapsed neuroblastoma is clinically heterogeneous and highlight the need for better biomarkers to optimize patient care. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 11/2012; 60(3). · 2.35 Impact Factor
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    ABSTRACT: MYCN-amplification is strongly associated with other high-risk prognostic factors and poor outcome in neuroblastoma. Infrequently, amplification of MYCN has been identified in localized tumors with favorable biologic features. Outcome for these children is difficult to predict and optimal treatment strategies remain unclear. We report a 5-month-old who presented with an MYCN-amplified INSS stage 3, pelvic neuroblastoma. The tumor had favorable histology, hyperdiploidy, and lacked 1p36 and 11q23 aberrations. Although the patient met the criteria for high-risk neuroblastoma, because of the discordant prognostic markers we elected to treat her according to an intermediate-risk protocol. She remains event-free more than 18 months.
    Pediatric Blood & Cancer 10/2012; 59(4):736-8. · 2.35 Impact Factor
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    ABSTRACT: Mutants of superoxide dismutase type 1 (mtSOD1) that have full dismutase activity (e.g., G37R) as well as none (e.g., G85R) cause familial amyotrophic lateral sclerosis (FALS), indicating that mtSOD1-induced FALS results from a toxicity rather than loss in SOD1 enzymatic activity. Still, it has remained unclear whether mtSOD1 dismutase activity can influence disease. A previous study demonstrated that Cre-mediated knockdown of G37R expression in Schwann cells (SCs) of G37R transgenic mice shortened the late phase of disease and survival. These results suggested that the neuroprotective effect of G37R expressed in SCs was greater than its toxicity, presumably because its dismutase activity counteracted reactive oxygen species (ROS). In order to further investigate this, we knocked down G85R in SCs by crossing G85R(flox) mice with myelin-protein-zero (P(0)):Cre mice, which express Cre recombinase in SCs. Knockdown of G85R in SCs of G85R mice delayed disease onset and extended survival indicating that G85R expression in SCs is neurotoxic. These results demonstrate differences in the effect on disease of dismutase active vs. inactive mtSOD1 suggesting that both a loss as well as gain in function of mtSOD1 influence FALS pathogenesis. The results suggest that mtSOD1-induced FALS treatment may have to be adjusted depending on the cell type targeted and particular mtSOD1 involved.
    Neurobiology of Disease 06/2012; 48(1):52-7. · 5.62 Impact Factor
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    ABSTRACT: Papillary tumor of the pineal region (PTPR) is a recently recognized entity. We present the pathologic findings of two cases of PTPR as examples, and discuss the presence of cellular pleomorphism in these tumors. Patient 1 is a 48-year-old man with a pineal region mass. The tumor had unique biphasic patterns, papillary/pseudopapillary areas, and increased mitotic activity. Juxtaposed areas had marked pleomorphism, including nuclear enlargement, smudgy chromatin, nuclear pseudoinclusions, and cytoplasmic vacuolation. Mitoses were absent in these areas. Immunohistochemical staining revealed strong S100 expression. CAM 5.2 and CK18 were strongly positive in a patchy fashion. MIB1 labeling indices were high in classic PTPR regions but very low in pleomorphic areas. Patient 2 was a 35-year-old male with a pineal region tumor characterized by papillary architecture and overall cellular monotony, rare mitoses, and pleomorphism as a more isolated finding, with associated nuclear enlargement and crowding. S100 and CAM 5.2 labeling were present, and MIB1 labeling index was very low throughout the tumor. We discuss the pathologic and phenotypic features of PTPR. Variable pleomorphism may be present, reflected in size variation and nuclear hyperchromasia, but was not accompanied by increased proliferative activity in these cases, suggesting a degenerative phenomenon.
    Brain Tumor Pathology 05/2012; · 1.58 Impact Factor

Publication Stats

634 Citations
254.60 Total Impact Points

Institutions

  • 2008–2015
    • University of Illinois at Chicago
      • • Department of Pathology (Chicago)
      • • Department of Pediatrics (Chicago)
      Chicago, Illinois, United States
  • 2014
    • Argonne National Laboratory
      Lemont, Illinois, United States
  • 2005–2014
    • The University of Chicago Medical Center
      • Department of Pathology
      Chicago, Illinois, United States
    • University of Chicago
      • • Department of Pathology
      • • Department of Medicine
      Chicago, Illinois, United States