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Gilbert R.J.C.,University of Oxford | Mikelj M.,University of Ljubljana | Dalla Serra M.,National Research Council Italy | Froelich C.J.,NorthShore University HealthSystem Research Institute | And 2 more authors.
Cellular and Molecular Life Sciences | Year: 2013

Recent work on the MACPF/CDC superfamily of pore-forming proteins has focused on the structural analysis of monomers and pore-forming oligomeric complexes. We set the family of proteins in context and highlight aspects of their function which the direct and exclusive equation of oligomers with pores fails to explain. Starting with a description of the distribution of MACPF/CDC proteins across the domains of life, we proceed to show how their evolutionary relationships can be understood on the basis of their structural homology and re-evaluate models for pore formation by perforin, in particular. We furthermore highlight data showing the role of incomplete oligomeric rings (arcs) in pore formation and how this can explain small pores generated by oligomers of proteins belonging to the family. We set this in the context of cell biological and biophysical data on the proteins' function and discuss how this helps in the development of an understanding of how they act in processes such as apicomplexan parasites gliding through cells and exiting from cells. © 2012 Springer Basel AG.

Drobyshevsky A.,NorthShore University HealthSystem Research Institute | Jiang R.,NorthShore University HealthSystem Research Institute | Lin L.,NorthShore University HealthSystem Research Institute | Derrick M.,NorthShore University HealthSystem Research Institute | And 3 more authors.
Annals of Neurology | Year: 2014

Objective White matter (WM) injury due to myelination defects is believed to be responsible for the motor deficits seen in cerebral palsy. We tested the hypothesis that the predominant injury is to functional electrical connectivity in unmyelinated WM fibers by conducting a longitudinal study of central WM tracts in newborn rabbit kits with hypertonia in our model of cerebral palsy. Methods Pregnant rabbits at 70% gestation underwent 40-minute uterine ischemia. Motor deficits in newborn kits, including muscle hypertonia, were assessed by neurobehavioral testing. Major central WM tracts, including internal capsule, corpus callosum, anterior commissure, and fimbria hippocampi, were investigated for structural and functional injury using diffusion tensor magnetic resonance imaging (MRI), electrophysiological recordings of fiber conductivity in perfused brain slices, electron microscopy, and immunohistochemistry of oligodendrocyte lineage. Results Motor deficits were observed on postnatal day 1 (P1) when WM tracts were unmyelinated. Myelination occurred later and was obvious by P18. Hypertonia was associated with microstructural WM injury and unmyelinated axon loss at P1, diagnosed by diffusion tensor MRI and electron microscopy. Axonal conductivity from electrophysiological recordings in hypertonic P18 kits decreased only in unmyelinated fibers, despite a loss in both myelinated and unmyelinated axons. Interpretation Motor deficits in cerebral palsy were associated with loss of unmyelinated WM tracts. The contribution of injury to myelinated fibers that was observed at P18 is probably a secondary etiological factor in the motor and sensory deficits in the rabbit model of cerebral palsy. Ann Neurol 2014;75:533-541 © 2014 American Neurological Association.

Sahasrabuddhe A.A.,NorthShore University HealthSystem Research Institute | Dimri M.,NorthShore University HealthSystem Research Institute | Dimri M.,George Washington University | Bommi P.V.,NorthShore University HealthSystem Research Institute | And 2 more authors.
Cell Cycle | Year: 2011

The polycomb group protein BMI1 has been linked to proliferation, senescence, cancer progression and stem cell phenotype. At present, very little is known about its regulation. Here, we report that BMI1 contains a functional recognition motif for the F box protein βTrCP, which regulates ubiquitination and proteasome-mediated degradation of various proteins. We show that overexpression of wild-type βTrCP but not the ΔF mutant of it promotes BMI1 ubiquitination and degradation, and knockdown of βTrCP results in increased expression of BMI1. Furthermore, a mutant of BMI1 with an altered βTrCP recognition motif is much more stable than wild-type BMI1. We also show that wild-type BMI1 but not the mutant BMI1 interacts with βTrCP. Accordingly, compared to wild-type BMI1, mutant protein exhibited increased prooncogenic activity. In summary, our findings suggest that βTrCP regulates turnover of BMI1 and its function relevant to oncogenesis, cellular senescence and aging. © 2011 Landes Bioscience.

Dimri M.,NorthShore University HealthSystem Research Institute | Bommi P.V.,NorthShore University HealthSystem Research Institute | Sahasrabuddhe A.A.,NorthShore University HealthSystem Research Institute | Khandekar J.D.,NorthShore University HealthSystem Research Institute | Dimri G.P.,NorthShore University HealthSystem Research Institute
Carcinogenesis | Year: 2010

The polycomb group (PcG) protein, enhancer of zeste homologue 2 (EZH2), is overexpressed in several human malignancies including breast cancer. Aberrant expression of EZH2 has been associated with metastasis and poor prognosis in cancer patients. Despite the clear role of EZH2 in oncogenesis and therapy failure, not much is known about chemotherapeutics and chemopreventive agents that can suppress its expression and activity. Here, we show that dietary omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) can regulate the expression of EZH2 in breast cancer cells. The treatment of breast cancer cells with v-3 PUFAs, but not ω-6 PUFAs, led to downregulation of EZH2. Studies using proteosome inhibitor MG132 suggested that ω-3 PUFAs induce degradation of the PcG protein EZH2 through posttranslational mechanisms. Furthermore, downregulation of EZH2 by ω-3 PUFAs was accompanied by a decrease in histone 3 lysine 27 trimethylation (H3K27me3) activity of EZH2 and upregulation of E-cadherin and insulin-like growth factor binding protein 3, which are known targets of EZH2. Treatment with ω-3 PUFAs also led to decrease in invasion of breast cancer cells, an oncogenic phenotype that is known to be associated with EZH2. Thus, our studies suggest that the PcG protein EZH2 is an important target of ω-3 PUFAs and that downregulation of EZH2 may be involved in the mediation of anti-oncogenic and chemopreventive effects of ω-3 PUFAs. © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

Halin S.,Umeå University | Rudolfsson S.H.,Umeå University | Doll J.A.,NorthShore University HealthSystem Research Institute | Crawford S.E.,NorthShore University HealthSystem Research Institute | And 2 more authors.
Neoplasia | Year: 2010

Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis but whether it has additional effects on the tumor microenvironment is largely unexplored. We show that overexpression of PEDF in orthotopic MatLyLu rat prostate tumors increased tumor macrophage recruitment. The fraction of macrophages expressing inducible nitric oxide synthase, a marker of cytotoxic M1 macrophages, was increased, suggesting that PEDF could enhance antitumor immunity. In addition, PEDF overexpression reduced vascular growth both in the tumor and in the surrounding normal tissue, slowed tumor growth, and decreased lymph node metastasis. Contrary, extratumoral lymphangiogenesis was increased. PEDF expression is, for reasons unknown, often decreased or lost during prostate tumor progression. When AT-1 rat prostate tumor cells, expressing high levels of PEDF messenger RNA (mRNA) and protein, were injected into the prostate, PEDF is markedly downregulated, suggesting that factors in the microenvironment suppressed its expression. One such factor could be macrophage-derived tumor necrosis factor α (TNFα). A fraction of the accumulating macrophages expressed TNFα, and TNFα treatment downregulated the expression of PEDF protein and mRNA in prostate AT-1 tumor cells in vitro and in the rat ventral prostate in vivo. PEDF apparently has multiple effects in prostate tumors: it suppresses angiogenesis and metastasis, but it also causes macrophage accumulation. Accumulating macrophages may inhibit tumor growth, but they may also suppress PEDF and enhance lymph angiogenesis and, in this way, eventually enhance tumor growth. © 2010 Neoplasia Press, Inc.

Bommi P.V.,NorthShore University HealthSystem Research Institute | Dimri M.,NorthShore University HealthSystem Research Institute | Sahasrabuddhe A.A.,NorthShore University HealthSystem Research Institute | Khandekar J.D.,NorthShore University HealthSystem Research Institute | Dimri G.P.,NorthShore University HealthSystem Research Institute
Cell Cycle | Year: 2010

Polycomb group (PcG) proteins are overexpressed in several human malignancies including breast cancer. In particular, aberrant expression of BMI1 and EZH2 has been linked to metastasis and poor prognosis in cancer patients. At present, very little is known about the pharmacological inhibitors of PcG proteins. Here we show that histone deacetylase inhibitors (HDACi) downregulate expression of BMI1. Treatment of MCF10A cells, which are immortal non-transformed breast epithelial cells, and breast cancer cells with HDACi led to decreased expression of BMI1. We further show that downregulation of BMI1 by HDACi results due to the transcriptional downregulation of BMI1 gene. Specifically, we show that primary transcription and promoter activity of BMI1 is suppressed upon treatment with HDACi. Furthermore, downregulation of BMI1 was accompanied by a decrease in histone 2A lysine 119 ubiquitination (H2AK119Ub), which is catalyzed by BMI1 containing polycomb repressive complex 1. HDACi treatment also led to derepression of growth inhibitory genes and putative tumor suppressors, which are known to be silenced by PcG proteins and polycomb repressive complexes (prCs). In summary, our findings suggest that BMI1 is an important therapy target of HDACi, and that HDACi can be used alone or in combination with other therapies to inhibit growth of tumors that overexpress PcG proteins such as BMI1. © 2010 Landes Bioscience.

Wang E.E.,NorthShore University HealthSystem | Dyne P.L.,View Medical | Du H.,NorthShore University HealthSystem Research Institute
Academic Emergency Medicine | Year: 2011

Objectives: The development of robust Accreditation Council for Graduate Medical Education (ACGME) systems-based practice (SBP) training and validated evaluation tools has been generally challenging for emergency medicine (EM) residency programs. The purpose of this paper is to report the results of a consensus workgroup session of the 2010 Council of Emergency Medicine Residency Directors (CORD) Academic Assembly with the following objectives: 1) to discuss current and preferred local and regional methods for teaching and assessing SBP and 2) to develop consensus within the CORD community using the modified Delphi method with respect to EM-specific SBP domains and link these domains to specific SBP educational and evaluative methods. Methods: Consensus was developed using a modified Delphi method. Previously described taxonomy generation methodology was used to create a SBP taxonomy of EM domain-specific knowledge, skills, and attitudes (KSA). The steps in the process consisted of: 1) an 11-question preconference survey, 2) a vetting process conducted at the 2010 CORD Academic Assembly, and 3) the development and ranking of domain-specific SBP educational activities and evaluation criteria for the specialty of EM. Results: Rank-order lists were created for preferred SBP education and evaluation methods. Expert modeling, informal small group discussion, and formal small group activities were considered to be the optimal methods to teach SBP. Kruskal-Wallis testing revealed that these top three items were rated significantly higher than self-directed learning projects and lectures (p = 0.0317). Post hoc test via permutation testing revealed that the difference was significant between expert modeling and formal small group activity (adjusted p = 0.028), indicating that expert modeling was rated significantly higher than formal small group activity. Direct observation methods were the preferred methods for evaluation. Multiple barriers to training and evaluation were elucidated. We developed a consensus taxonomy of domains that were felt to be most essential and reflective of the practice of EM: multitasking, disposition, and patient safety. Learning formats linked to the domains were created and specific examples of local best practices collected. Domain-specific anchors of observable actions for the three domains were created. Conclusions: This consensus process resulted in the development of a taxonomy of EM-specific domains for teaching and observable tasks for evaluating SBP. The concept of SBP is interlinked with the other general competencies and difficult to separate. Rather than develop specific SBP evaluation tools to measure the competency directly, SBP competency evaluation should be considered one element of a coordinated effort to teach and evaluate the six ACGME general competencies. © 2011 by the Society for Academic Emergency Medicine.

Drobyshevsky A.,NorthShore University HealthSystem Research Institute | Jiang R.,NorthShore University HealthSystem Research Institute | Derrick M.,NorthShore University HealthSystem Research Institute | Luo K.,NorthShore University HealthSystem Research Institute | Tan S.,NorthShore University HealthSystem Research Institute
Experimental Neurology | Year: 2014

Anisotropy indices derived from diffusion tensor imaging (DTI) are being increasingly used as biomarkers of central WM structural maturation, myelination and even functional development. Our hypothesis was that the rate of functional changes in central WM tracts directly reflects rate of changes in structural development as determined by DTI indices. We examined structural and functional development of four major central WM tracts with different maturational trajectories, including internal capsule (IC), corpus callosum (CC), fimbria hippocampi (FH) and anterior commissure (AC). Rabbits were chosen due to perinatal brain development being similar to humans, and four time points were studied: P1, P11, P18 and adults. Imaging parameters of structural maturation included fractional anisotropy (FA), mean and directional diffusivities derived from DTI, and T2 relaxation time. Axonal composition and degree of myelination were confirmed on electron microscopy. To assess functional maturation, conduction velocity was measured in myelinated and non-myelinated fibers by electrophysiological recordings of compound action potential in perfused brain slices. Diffusion indices and T2 relaxation time in rabbits followed a sigmoid curve during development similar to that for humans, with active changes even at premyelination stage. The shape of the developmental curve was different between the fiber tracts, with later onset but steeper rapid phase of development in IC and FH than in CC. The structural development was not directly related to myelination or to functional development. Functional properties in projection (IC) and limbic tracts (FH) matured earlier than in associative and commissural tracts (CC and AC).The rapid phase of changes in diffusion anisotropy and T2 relaxation time coincided with the development of functional responses and myelination in IC and FH between the second and third weeks of postnatal development in rabbits. In these two tracts, MRI indices could serve as surrogate markers of the early stage of myelination. However, the discordance between developmental change of diffusion indices, myelination and functional properties in CC and AC cautions against equating DTI index changes as biomarkers for myelination in all tracts. © 2014 Elsevier Inc.

Northshore University Healthsystem Research Institute and Siemens AG | Date: 2014-04-02

A method for operating a Magnetic Resonance (MR) imaging system including generating radio frequency (RF) excitation pulses in a volume of patient anatomy that includes a patients heart to provide subsequent acquisition of associated RF echo data and generating slice select magnetic field gradients for phase encoding and readout RF data acquisition in the volume of patient anatomy. The method also includes acquiring a plurality of slices of an image of the volume of patient anatomy within a plurality of cycles representing time period between successive beats of the patients heart. The method also includes causing, by a control processor, accelerated acquisition of two or more slices of the plurality of slices within a quiescent phase of each of the plurality of cycles. The method further includes applying, by the control processor, one or more saturation areas proximate to a target volume of the patient anatomy.

Silva A.K.,University of Chicago | Lapin B.,NorthShore University HealthSystem Research Institute | Yao K.A.,NorthShore University HealthSystem | Song D.H.,University of Chicago | Sisco M.,NorthShore University HealthSystem
Annals of Surgical Oncology | Year: 2015

Background: Women with breast cancer are increasingly choosing to undergo contralateral prophylactic mastectomy (CPM) despite questionable survival benefit and limited data on added risks. Little is known about differences in perioperative complications between women who undergo bilateral mastectomy (BM) versus unilateral mastectomy (UM) with reconstruction. Methods: The American College of Surgeons National Surgery Quality Improvement Program Participant Use Files (2005–2013) were used to identify women with unilateral breast cancer who underwent UM or BM with reconstruction. Adjusted 30-day complications were compared between UM and BM groups using logistic regression models. Results: A total of 20,501 patients were identified, of whom 35.3 % underwent BM. Of these, 84.3 % had implant reconstruction and 15.7 % had autologous reconstruction. For all women, BM was associated with longer hospital stays (adjusted odds ratio [aOR] 1.98–2.09, p < 0.001) and a higher transfusion rate than UM (aOR 2.52–3.06, p < 0.001). BM with implant reconstruction was associated with a modestly increased reoperation rate (aOR 1.15, p = 0.029). BM with autologous reconstruction was associated with a higher wound disruption rate (aOR 2.51, p = 0.015). Surgical site infections, prosthesis failure, and medical complications occurred at similar rates in UM and BM groups. Conclusions: CPM is associated with significant increases in some, but not all, surgical site complications. CPM does not increase the likelihood of medical complications, which are generally infrequent. © 2015, Society of Surgical Oncology.

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