Medicine and Health Sciences Commons^™

Thomas Jefferson University, Department Of Pathology, Anatomy And Cell Biology, Oral Administration Of Apigenin Inhibits Metastasis Through Akt/P70s6k1/Mmp-9 Pathway In Orthotopic Ovarian Tumor Model., Jun He, Qing Xu, Min Wang, Chongyong Li, Xu Qian, Zhumei Shi, Ling-Zhi Liu, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Apigenin, a flavonoid commonly present in the daily diet, is known for its potential anti-tumor properties. However, the effect of apigenin via oral administration on tumor growth and metastasis remains unknown. In this study we developed an orthotopic ovarian tumor model in nude mice to test the effect of apigenin oral administration, and showed that apigenin inhibited the micrometastasis of cancer cells in the animal tumor model. To understand the mechanism of apigenin in inhibiting metastasis, we found that apigenin greatly inhibited MMP-9 expression and p-AKT and p-p70S6K1 levels in the tumor tissues compared to the control group. We further …

Loss Of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration And Alzheimer's Disease-Related Tau Phosphorylation Via Par-1., Kanae Iijima-Ando, Michiko Sekiya, Akiko Maruko-Otake, Yosuke Ohtake, Emiko Suzuki, Bingwei Lu, Koichi M Iijima

Farber Institute for Neuroscience Faculty Papers

Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD); however, what pathological conditions trigger tau abnormality in AD is not fully understood. A reduction in the number of mitochondria in the axon has been implicated in AD. In this study, we investigated whether and how loss of axonal mitochondria promotes tau phosphorylation and toxicity in vivo. Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 …

Glucose Decouples Intracellular Ca2+ Activity From Glucagon Secretion In Mouse Pancreatic Islet Alpha-Cells., Sylvain J Le Marchand, David W Piston

Farber Institute for Neuroscience Faculty Papers

The mechanisms of glucagon secretion and its suppression by glucose are presently unknown. This study investigates the relationship between intracellular calcium levels ([Ca(2+)](i)) and hormone secretion under low and high glucose conditions. We examined the effects of modulating ion channel activities on [Ca(2+)](i) and hormone secretion from ex vivo mouse pancreatic islets. Glucagon-secreting α-cells were unambiguously identified by cell specific expression of fluorescent proteins. We found that activation of L-type voltage-gated calcium channels is critical for α-cell calcium oscillations and glucagon secretion at low glucose levels. Calcium channel activation depends on K(ATP) channel activity but not on tetrodotoxin-sensitive Na(+) channels. …

Larynx-Sparing Techniques Using Intensity-Modulated Radiation Therapy For Oropharyngeal Cancer., Voichita Bar-Ad, Haibo Lin, Wei-Ting Hwang, Curtiland Deville, Pinaki R Dutta, Zelig Tochner, Stefan Both

Department of Radiation Oncology Faculty Papers

The purpose of the current study was to explore whether the laryngeal dose can be reduced by using 2 intensity-modulated radiation therapy (IMRT) techniques: whole-neck field IMRT technique (WF-IMRT) vs. junctioned IMRT (J-IMRT). The effect on planning target volumes (PTVs) coverage and laryngeal sparing was evaluated. WF-IMRT technique consisted of a single IMRT plan, including the primary tumor and the superior and inferior neck to the level of the clavicular heads. The larynx was defined as an organ at risk extending superiorly to cover the arytenoid cartilages and inferiorly to include the cricoid cartilage. The J-IMRT technique consisted of an …

Gene Expression Signatures Modulated By Epidermal Growth Factor Receptor Activation And Their Relationship To Cetuximab Resistance In Head And Neck Squamous Cell Carcinoma., Elana J Fertig, Qing Ren, Haixia Cheng, Hiromitsu Hatakeyama, Adam Dicker Md, Phd, Ulrich Rodeck, Michael Considine, Michael F Ochs, Christine H Chung

Department of Radiation Oncology Faculty Papers

BACKGROUND: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D.

RESULTS: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity …

Testosterone Treatment Fails To Accelerate Disease In A Transgenic Mouse Model Of Spinal And Bulbar Muscular Atrophy., Erica S Chevalier-Larsen, Diane E Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Evidence from multiple animal models demonstrates that testosterone plays a crucial role in the progression of symptoms in spinal and bulbar muscular atrophy (SBMA), a condition that results in neurodegeneration and muscle atrophy in affected men. Mice bearing a transgene encoding a human androgen receptor (AR) that contains a stretch of 112 glutamines (expanded polyglutamine tract; AR112Q mice) reproduce several aspects of the human disease. We treated transgenic male AR112Q mice with testosterone for 6 months. Surprisingly, testosterone treatment of AR112Q males did not exacerbate the disease. Although transgenic AR112Q males exhibited functional deficits when compared with non-transgenics, long-term testosterone …

Mitochondrial Lysyl-Trna Synthetase Independent Import Of Trna Lysine Into Yeast Mitochondria., Naresh Babu V Sepuri, Madhavi Gorla, Michael P King

Department of Biochemistry and Molecular Biology Faculty Papers

Aminoacyl tRNA synthetases play a central role in protein synthesis by charging tRNAs with amino acids. Yeast mitochondrial lysyl tRNA synthetase (Msk1), in addition to the aminoacylation of mitochondrial tRNA, also functions as a chaperone to facilitate the import of cytosolic lysyl tRNA. In this report, we show that human mitochondrial Kars (lysyl tRNA synthetase) can complement the growth defect associated with the loss of yeast Msk1 and can additionally facilitate the in vitro import of tRNA into mitochondria. Surprisingly, the import of lysyl tRNA can occur independent of Msk1 in vivo. This suggests that an alternative mechanism is present …

Synergetic Effect Of Recoverin And Calmodulin On Regulation Of Rhodopsin Kinase., Ilya I Grigoriev, Ivan I Senin, Natalya K Tikhomirova, Konstantin E Komolov, Sergei E Permyakov, Evgeni Yu Zernii, Karl-Wilhelm Koch, Pavel P Philippov

Department of Biochemistry and Molecular Biology Faculty Papers

Phosphorylation of photoactivated rhodopsin by rhodopsin kinase (RK or GRK1), a first step of the phototransduction cascade turnoff, is under the control of Ca(2+)/recoverin. Here, we demonstrate that calmodulin, a ubiquitous Ca(2+)-sensor, can inhibit RK, though less effectively than recoverin does. We have utilized the surface plasmon resonance technology to map the calmodulin binding site in the RK molecule. Calmodulin does not interact with the recoverin-binding site within amino acid residues M1-S25 of the enzyme. Instead, the high affinity calmodulin binding site is localized within a stretch of amino acid residues V150-K175 in the N-terminal regulatory region of RK. Moreover, …

Genes Adopt Non-Optimal Codon Usage To Generate Cell Cycle-Dependent Oscillations In Protein Levels., Milana Frenkel-Morgenstern, Tamar Danon, Thomas Christian, Takao Igarashi, Lydia Cohen, Ya-Ming Hou, Lars Juhl Jensen

Department of Biochemistry and Molecular Biology Faculty Papers

The cell cycle is a temporal program that regulates DNA synthesis and cell division. When we compared the codon usage of cell cycle-regulated genes with that of other genes, we discovered that there is a significant preference for non-optimal codons. Moreover, genes encoding proteins that cycle at the protein level exhibit non-optimal codon preferences. Remarkably, cell cycle-regulated genes expressed in different phases display different codon preferences. Here, we show empirically that transfer RNA (tRNA) expression is indeed highest in the G2 phase of the cell cycle, consistent with the non-optimal codon usage of genes expressed at this time, and lowest …

Lymph Node Ratio Is An Important And Independent Prognostic Factor For Patients With Stage Iii Melanoma., Adam C. Berger, Michael Fierro, John C Kairys, David Berd, Takami Sato, Jocelyn Andrel, Terry Hyslop, Michael J Mastrangelo

Department of Surgery Faculty Papers

INTRODUCTION: The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients.

METHODS: We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n = 93; 10-≤25%, n = 45; and >25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model.

RESULTS: The median survival time of …

Right Ventricular Rupture And Tamponade Caused By Malposition Of The Avalon Cannula For Venovenous Extracorporeal Membrane Oxygenation., Hitoshi Hirose, Kentaro Yamane, Gregary D. Marhefka, Nicholas C. Cavarocchi

Department of Surgery Faculty Papers

Placement of the Avalon Elite bicaval dual lumen cannula for venovenous extracorporeal membrane oxygenation (VV-ECMO) via the internal jugular vein requires precise positioning of the cannula tip in the inferior vena cava with echocardiography or fluoroscopy guidance. Correct guidewire placement is clearly the key first step in assuring proper advancement of the cannula. We report a case of unexpected wire migration into the right ventricle at the time of final cannula advancement, resulting in right ventricular rupture and tamponade. Transesophageal echocardiography is an important monitoring modality for appropriate placement of the VV-ECMO guidewire and Avalon cannula, and in particular, for …

Preoperative Fdg-Pet/Ct Is An Important Tool In The Management Of Patients With Thick (T4) Melanoma., Rodrigo Arrangoiz, Pavlos Papavasiliou, Carrie A Stransky, Jian Q Yu, Li Tianyu, Elin R Sigurdson, Adam C. Berger, Jeffrey M Farma

Department of Surgery Faculty Papers

The yield of preoperative PET/CT (PET/CT) for regional and distant metastases for thin/intermediate thickness melanoma is low. Objective of this study is to determine if PET/CT performed for T4 melanomas helps guide management and alter treatment plans. Methods. Retrospective cohort of 216 patients with T4 melanomas treated at two tertiary institutions. Fifty-six patients met our inclusion criteria (T4 lesion, PET/CT and no clinical evidence of metastatic disease). Results. Fifty-six patients (M: 32, F: 24) with median tumor thickness of 6 mm were identified. PET/CT recognized twelve with regional and four patients with metastatic disease. Melanoma-related treatment plan was altered in …

Mir-145 Directly Targets P70s6k1 In Cancer Cells To Inhibit Tumor Growth And Angiogenesis., Qing Xu, Ling-Zhi Liu, Xu Qian, Qi Chen, Yue Jiang, Dan Li, Lihui Lai, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

MiR-145 can regulate cell apoptosis, proliferation, neural development and stem cell differentiation. Previous studies indicate that miR-145 is downregulated in human colon cancer cells. However, the molecular mechanisms of miR-145 used to regulate colon carcinogenesis and angiogenesis remain to be clarified. Here, we show that the expression of miR-145 is downregulated in colon and ovarian cancer tissues and cell lines. MiR-145 inhibits p70S6K1 post-transcriptional expression by binding to its 3'-UTR. The angiogenic factors hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF), which are downstream molecules of p70S6K1, are decreased by miR-145 overexpression. P70S6K1 rescues miR-145-suppressed HIF-1 and VEGF …

Blood-Brain Barrier Abnormalities Caused By Hiv-1 Gp120: Mechanistic And Therapeutic Implications., Jean-Pierre Louboutin, David S Strayer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and …

Graft Versus Host Disease Of The Brain Following Allogeneic Stem Cell Transplant For Myelodysplastic Syndrome, Janet Yoo, Lindsay Simon, Zi-Xuan Wang, Phd, Lawrence C. Kenyon

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Graft-versus-host disease (GVHD) is a frequent cause of morbidity and mortality following bone marrow transplantation (BMT). GVHD occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. GVHD, which can present either acutely or chronically, typically involves the skin, gastrointestinal tract, and liver. In contrast, GVHD involving other organs such as the heart and kidney is highly uncommon and involvement of the central nervous system has only very rarely been described in the literature. We report an unusual case …

Integrative Gene Regulatory Network Analysis Reveals Light-Induced Regional Gene Expression Phase Shift Programs In The Mouse Suprachiasmatic Nucleus., Haisun Zhu, Rajanikanth Vadigepalli, Rachel Rafferty, Gregory E Gonye, David R Weaver, James S Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

We use the multigenic pattern of gene expression across suprachiasmatic nuclei (SCN) regions and time to understand the dynamics within the SCN in response to a circadian phase-resetting light pulse. Global gene expression studies of the SCN indicate that circadian functions like phase resetting are complex multigenic processes. While the molecular dynamics of phase resetting are not well understood, it is clear they involve a "functional gene expression program", e.g., the coordinated behavior of functionally related genes in space and time. In the present study we selected a set of 89 of these functionally related genes in order to further …

Lung Carcinoma In The Era Of Personalized Medicine: The Role Of Cytology., Maureen F Zakowski, Marluce Bibbo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

In 2004, three groups working independently [1–3] , almost simultaneously, reported remarkable findings: that activating mutations in the epidermal growth factor receptor (EGFR) were common in certain lung carcinomas and that these mutations correlated with the response of those lung tumors to therapy with gefitinib and erlotinib, both EGFR tyrosine kinase inhibitors (TKIs). This was the first time driver mutations in lung cancer that responded to targeted therapy had been identified, marking the beginning of a new era of personalized medicine in lung cancer. Prior to the discovery of these mutations, patients had been treated with EGFR TKIs but predicting …

Cop9 Signalosome Component Jab1/Csn5 Is Necessary For T Cell Signaling Through Lfa-1 And Hiv-1 Replication., Shigemi M Kinoshita, Peter O Krutzik, Garry P Nolan

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication. A large library of short peptide aptamers was expressed via retroviral delivery in T cells. Peptides that interfered with T cell activation-dependent processes that might support HIV-1 replication were identified. One of the selected peptides altered signaling, lead to a difference in T cell activation status, and inhibited HIV-1 replication. The target of the peptide was JAB1/CSN5, a component of the signalosome complex. JAB1 expression overcame the inhibition of HIV-1 replication in the presence …

Knockdown Of Ki-67 By Dicer-Substrate Small Interfering Rna Sensitizes Bladder Cancer Cells To Curcumin-Induced Tumor Inhibition., Sivakamasundari Pichu, Swapna Krishnamoorthy, Andrei Shishkov, Bi Zhang, Peter Mccue, Biddanda C Ponnappa

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Transitional cell carcinoma (TCC) of the urinary bladder is the most common cancer of the urinary tract. Most of the TCC cases are of the superficial type and are treated with transurethral resection (TUR). However, the recurrence rate is high and the current treatments have the drawback of inducing strong systemic toxicity or cause painful cystitis. Therefore, it would be of therapeutic value to develop novel concepts and identify novel drugs for the treatment of bladder cancer. Ki-67 is a large nucleolar phosphoprotein whose expression is tightly linked to cell proliferation, and curcumin, a phytochemical derived from the rhizome Curcuma …

The Dermatan Sulfate Proteoglycan Decorin Modulates Α2Β1 Integrin And The Vimentin Intermediate Filament System During Collagen Synthesis., Oliver Jungmann, Katerina Nikolovska, Christian Stock, Jan-Niklas Schulz, Beate Eckes, Christoph Riethmüller, Rick T Owens, Renato V Iozzo, Daniela G Seidler

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn(-/-)) mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn(-/-) mice could be rescued in vitro by decorin but not with decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn(-/-) fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, …

Decorin Protein Core Affects The Global Gene Expression Profile Of The Tumor Microenvironment In A Triple-Negative Orthotopic Breast Carcinoma Xenograft Model., Simone Buraschi, Thomas Neill, Rick T Owens, Leonardo A Iniguez, George Purkins, Rajanikanth Vadigepalli, Barry Evans, Liliana Schaefer, Stephen C Peiper, Zi-Xuan Wang, Renato V Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that …

Kaempferol Nanoparticles Achieve Strong And Selective Inhibition Of Ovarian Cancer Cell Viability., Haitao Luo, Bingbing Jiang, Bingyun Li, Zhaoliang Li, Bing-Hua Jiang, Yi Charlie Chen

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Ovarian cancer is one of the leading causes of cancer death for women throughout the Western world. Kaempferol, a natural flavonoid, has shown promise in the chemoprevention of ovarian cancer. A common concern about using dietary supplements for chemoprevention is their bioavailability. Nanoparticles have shown promise in increasing the bioavailability of some chemicals. Here we developed five different types of nanoparticles incorporating kaempferol and tested their efficacy in the inhibition of viability of cancerous and normal ovarian cells. We found that positively charged nanoparticle formulations did not lead to a significant reduction in cancer cell viability, whereas nonionic polymeric nanoparticles …

Temporal Changes In Innate Immune Signals In A Rat Model Of Alcohol Withdrawal In Emotional And Cardiorespiratory Homeostatic Nuclei., Kate Freeman, Anthony Brureau, Rajanikanth Vadigepalli, Mary M Staehle, Melanie M Brureau, Gregory E Gonye, Jan B Hoek, D Craig Hooper, James S Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Chronic alcohol use changes the brain's inflammatory state. However, there is little work examining the progression of the cytokine response during alcohol withdrawal, a period of profound autonomic and emotional upset. This study examines the inflammatory response in the central nucleus of the amygdala (CeA) and dorsal vagal complex (DVC), brain regions neuroanatomically associated with affective and cardiorespiratory regulation in an in vivo rat model of withdrawal following a single chronic exposure.

METHODS: For qRT-PCR studies, we measured the expression of TNF-α, NOS-2, Ccl2 (MCP-1), MHC II invariant chain CD74, and the TNF receptor Tnfrsf1a in CeA and DVC …

Emergence Of Bimodal Cell Population Responses From The Interplay Between Analog Single-Cell Signaling And Protein Expression Noise., Marc R Birtwistle, Jens Rauch, Anatoly Kiyatkin, Edita Aksamitiene, Maciej Dobrzyński, Jan B. Hoek, Walter Kolch, Babatunde A Ogunnaike, Boris N Kholodenko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Cell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic and probabilistic models and biochemical measurements to study how network topologies and cell-to-cell protein abundance variations interact to shape signaling responses.

RESULTS: We observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses to epidermal growth factor (EGF) stimulation, which are generally thought to indicate bistable or ultrasensitive signaling behavior in single cells. Surprisingly, we find that a simple MAPK/ERK-cascade model with negative feedback that displays graded, analog ERK responses at a single cell level can explain the experimentally …

Boerhaave's Syndrome As A First Presentation Of Eosinophilic Esophagitis, Whitney E. Jackson, Vaibhav Mehendiratta, Juan P. Palazzo, Anthony J. Dimarino, Sidney Cohen

Division of Internal Medicine Faculty Papers & Presentations

Purpose: Prior studies have reported esophageal rupture following endoscopy or bolus impaction in eosinophilic esophagitis. The purpose of this study is to examine the frequency and characteristics of spontaneous rupture (Boerhaave's Syndrome) associated with vomiting S-435 AGA Abstracts in eosinophilic esophagitis.

Methods: A retrospective search of inpatient and outpatient records was conducted for the diagnoses "Boerhaave's", "eosinophilic esophagitis", and "esophageal rupture" from January 2001 to January 2011 within the gastroenterology division at an urban tertiary care hospital. For each subject identified, medical records, endoscopy reports, biopsy reports and radiographic studies were reviewed. A faculty member of the Department of Pathology …

Conversion From Enzyme-Inducing Antiepileptic Drugs To Topiramate: Effects On Lipids And C-Reactive Protein., Scott Mintzer, Christopher T Skidmore, Sara J Rankin, Inna Chervoneva, Edward Pequinot, David M Capuzzi, Michael R Sperling

Department of Neurology Faculty Papers

PURPOSE: We previously demonstrated that converting patients from the enzyme-inducers phenytoin or carbamazepine to the non-inducers levetiracetam or lamotrigine reduces serum lipids and C-reactive protein (CRP). We sought to determine if the same changes would occur when patients were switched to topiramate, which has shown some evidence of enzyme induction at high doses. We also examined the effects of drug switch on low-density lipoprotein (LDL) particle concentration.

METHODS: We converted 13 patients from phenytoin or carbamazepine monotherapy to topiramate monotherapy (most at doses of 100-150 mg/day). Fasting lipids, including LDL particle concentration, and CRP were obtained before and ≥6 weeks …

Effect Of 4 Years Of Growth Hormone Therapy In Children With Noonan Syndrome In The American Norditropin Studies: Web-Enabled Research (Answer) Program® Registry., Peter A Lee, Judith Ross, John A Germak, Robert Gut

Department of Pediatrics Faculty Papers

BACKGROUND: Noonan syndrome (NS) is a genetic disorder characterized by phenotypic features, including facial dysmorphology, cardiovascular anomalies, and short stature. Growth hormone (GH) has been approved by the United States Food and Drug Administration for short stature in children with NS. The objective of this analysis was to assess the height standard deviation score (HSDS) and change in HSDS (ΔHSDS) for up to 4 years (Y4) of GH therapy in children with NS.

METHODS: The American Norditropin Studies: Web-Enabled Research (ANSWER) Program®, a US-based registry, collects long-term efficacy and safety information on patients treated with Norditropin® (somatropin rDNA origin, Novo …

Keratinocyte-Targeted Expression Of Human Laminin Γ2 Rescues Skin Blistering And Early Lethality Of Laminin Γ2 Deficient Mice., Tracy L Adair-Kirk, Gail L Griffin, Michelle J Meyer, Diane G Kelley, Jeffrey H Miner, Douglas R Keene, M Peter Marinkovich, J Michael Ruppert, Jouni Uitto, Robert M Senior

Department of Dermatology and Cutaneous Biology Faculty Papers

Laminin-332 is a heterotrimeric basement membrane component comprised of the α3, ß3, and γ2 laminin chains. Laminin-332 modulates epithelial cell processes, such as adhesion, migration, and differentiation and is prominent in many embryonic and adult tissues. In skin, laminin-332 is secreted by keratinocytes and is a key component of hemidesmosomes connecting the keratinocytes to the underlying dermis. In mice, lack of expression of any of the three Laminin-332 chains result in impaired anchorage and detachment of the epidermis, similar to that seen in human junctional epidermolysis bullosa, and death occurs within a few days after birth. To bypass the early …

Administration Of Bone Marrow Derived Mesenchymal Stem Cells Into The Liver: Potential To Rescue Pseudoxanthoma Elasticum In A Mouse Model (Abcc6-/-)., Qiujie Jiang, Shunsuke Takahagi, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

Pseudoxanthoma elasticum (PXE) is a heritable ectopic mineralization disorder caused by loss-of-function mutations in the ABCC6 gene which is primarily expressed in the liver. There is currently no effective treatment for PXE. In this study, we characterized bone marrow derived mesenchymal stem cells (MSCs) and evaluated their ability to contribute to liver regeneration, with the aim to rescue PXE phenotype. The MSCs, isolated from GFP-transgenic mice by magnetic cell sorting, were shown to have high potential for hepatic differentiation, with expression of Abcc6, in culture. These cells were transplanted into the livers of 4-week-old immunodeficient Abcc6⁻/⁻ mice by intrasplenic injection …

Cns Recruitment Of Cd8+ T Lymphocytes Specific For A Peripheral Virus Infection Triggers Neuropathogenesis During Polymicrobial Challenge., Christine M Matullo, Kevin J O'Regan, Mark Curtis, Glenn F Rall

Department of Microbiology and Immunology Faculty Papers

Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with …