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noonans disease

Argyrios Tzouvelekis, Guoying Yu, Christian Lacks Lino Cardenas, Jose D Herazo-Maya, Rong Wang, Tony Woolard, Yi Zhang, Koji Sakamoto, Hojin Lee, Jae-Sung Yi, Giuseppe DeIuliis, Nikolaos Xylourgidis, Farida Ahangari, Patty J Lee, Vassilis Aidinis, Erica L Herzog, Robert Homer, Anton M Bennett, Naftali Kaminski
RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and no cure. The potential role of the ubiquitously expressed SH2 domain-containing-tyrosine phosphatase (SHP2) as a therapeutic target has not been studied in IPF Objectives: To determine the expression, mechanistic role and potential therapeutic utility of SHP2 in Pulmonary Fibrosis Methods: The effects of SHP2 overexpression and inhibition on fibroblast response to pro-fibrotic stimuli were analyzed in-vitro in primary human and mouse lung fibroblasts...
October 13, 2016: American Journal of Respiratory and Critical Care Medicine
Jia Zhang, Ming Li, Zhirong Yao
Multiple café-au-lait macules (CALM) are usually associated with neurofibromatosis type 1 (NF1), one of the most common hereditary disorders. However, a group of genetic disorders presenting with CALM have mutations that are involved in human skin pigmentation regulation signaling pathways, including KIT ligand/KIT proto‑oncogene receptor tyrosine kinase and Ras/mitogen‑activated protein kinase. These disorders, which include Legius syndrome, Noonan syndrome with multiple lentigines or LEOPARD syndrome, and familial progressive hyperpigmentation) are difficult to distinguish from NF1 at early stages, using skin appearance alone...
September 22, 2016: Molecular Medicine Reports
Sinead A Noonan, Peter B Sachs, D Ross Camidge
INTRODUCTION: Osimertinib is an EGFR inhibitor licensed for the treatment of EGFR-mutant, T790M-positive NSCLC. Previously unreported, frequent transient asymptomatic pulmonary opacities were noted in patients during osimertinib therapy at the University of Colorado. METHODS: Computed tomography imaging and clinical notes on patients with NSCLC who had been treated with osimertinib at the University of Colorado were retrospectively reviewed. RESULTS: Transient asymptomatic pulmonary opacities developed in seven of 20 patients (35%) while they were receiving osimertinib...
September 13, 2016: Journal of Thoracic Oncology
J White, C Noonan-Toly, G Lukacik, N Thomas, A Hinckley, S Hook, P B Backenson
Despite the mandatory nature of Lyme disease (LD) reporting in New York State (NYS), it is believed that only a fraction of the LD cases diagnosed annually are reported to public health authorities. Lack of complete LD case reporting generally stems from (i) lack of report of provider-diagnosed cases where supportive laboratory testing is not ordered or results are negative (i.e. provider underreporting) and (ii) incomplete case information (clinical laboratory reporting only with no accompanying clinical information) such that cases are considered 'suspect' and not included in national and statewide case counts (i...
September 10, 2016: Zoonoses and Public Health
Paola Campomenosi, Elisabetta Gini, Douglas M Noonan, Albino Poli, Paola D'Antona, Nicola Rotolo, Lorenzo Dominioni, Andrea Imperatori
BACKGROUND: Selected microRNAs (miRNAs) that are abnormally expressed in the serum of patients with lung cancer have recently been proposed as biomarkers of this disease. The measurement of circulating miRNAs, however, requires a highly reliable quantification method. Quantitative real-time PCR (qPCR) is the most commonly used method, but it lacks reliable endogenous reference miRNAs for normalization of results in biofluids. When used in absolute quantification, it must rely on the use of external calibrators...
2016: BMC Biotechnology
Jorge E Cortes, Hanna J Khoury, Hagop M Kantarjian, Jeff H Lipton, Dong-Wook Kim, Philippe Schafhausen, Ewa Matczak, Eric Leip, Kay Noonan, Tim H Brümmendorf, Carlo Gambacorti-Passerini
Bosutinib is a Src/Abl tyrosine kinase inhibitor (TKI) indicated for adults with Ph+ chronic myeloid leukemia (CML) resistant/intolerant to prior TKIs. This long-term update of an ongoing phase 1/2 study evaluated the efficacy and safety of third-/fourth-line bosutinib in adults with chronic phase (CP) CML. Median durations of treatment and follow-up were 8.6 (range, 0.2-87.7) months and 32.7 (0.3-93.3) months, respectively. Cumulative confirmed complete hematologic response (cCHR) and major cytogenetic response (MCyR) rates were 74% (95% CI, 65%-81%) and 40% (31%-50%), respectively; Kaplan-Meier (K-M) probability of maintaining cCHR or MCyR at 4 years was 63% (95% CI, 50%-73%) and 69% (52%-81%)...
August 17, 2016: American Journal of Hematology
Haley R Noonan, Ana M Metelo, Caramai N Kamei, Randall T Peterson, Iain A Drummond, Othon Iliopoulos
Patients with von Hippel-Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. 'Clear cell' tumors contain large, proliferating cells with 'clear cytoplasm', and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis...
August 1, 2016: Disease Models & Mechanisms
Alexandre Arkader, Christopher Brusalis, William C Warner, James H Conway, Kenneth Noonan
Musculoskeletal infections, including osteomyelitis, septic arthritis, and pyomyositis, are a substantial cause of morbidity in children and adolescents. The increased virulence of infectious agents and the increased prevalence of antimicrobial-resistant pathogens, particularly methicillin-resistant Staphylococcus aureus, have resulted in a more complicated clinical course for diagnosis and management, which is evidenced by an increased length of hospital stays, incidence of complications, and number of surgical interventions...
September 2016: Journal of the American Academy of Orthopaedic Surgeons
Jaeger P Ackerman, John A Smestad, David J Tester, Muhammad Y Qureshi, Beau A Crabb, Nancy J Mendelsohn, Michael J Ackerman
OBJECTIVE: To use whole exome sequencing (WES) of a family trio to identify a genetic cause for polyvalvular syndrome. METHODS AND RESULTS: A male child was born with mild pulmonary valve stenosis and mild aortic root dilatation, and an atrial septal defect, ventricular septal defect, and patent ductus arteriosus that were closed surgically. Subsequently, the phenotype of polyvalvular syndrome with involvement of both semilunar and both atrioventricular valves emerged...
September 2016: Congenital Heart Disease
John Garcia, Jackie Tahiliani, Nicole Marie Johnson, Sienna Aguilar, Daniel Beltran, Amy Daly, Emily Decker, Eden Haverfield, Blanca Herrera, Laura Murillo, Keith Nykamp, Scott Topper
Advances in DNA sequencing have made large, diagnostic gene panels affordable and efficient. Broad adoption of such panels has begun to deliver on the promises of personalized medicine, but has also brought new challenges such as the presence of unexpected results, or results of uncertain clinical significance. Genetic analysis of inherited cardiac conditions is particularly challenging due to the extensive genetic heterogeneity underlying cardiac phenotypes, and the overlapping, variable, and incompletely penetrant nature of their clinical presentations...
2016: Frontiers in Cardiovascular Medicine
Urska Pevec, Neva Rozman, Blaz Gorsek, Tanja Kunej
Clinical symptoms often reflect molecular correlations between mutated proteins. Alignment between interactome and phenome levels reveals new disease genes and connections between previously unrelated diseases. Despite a great potential for novel discoveries, this approach is still rarely used in genomics. In the present study, we analyzed the data of 6 syndromes belonging to the RASopathy class of disorders (RASopathies) and presented them as a model to study associations between genome, interactome, and phenome levels...
May 2016: Molecular Syndromology
Hideki Muramatsu
Various genetic disorders are known to be associated with cancer predisposition. For example, children with Down syndrome are predisposed to developing acute myeloid leukemia, and those with RASopathies, such as Noonan syndrome, are predisposed to juvenile myelomonocytic leukemia. To date, more than 250 diseases or syndromes have been reported to be associated with the development of pediatric cancers. Recently, the advent of the massive parallel sequencing technique revealed several germline mutations, including RUNX1, CEBPA, GATA2, SRP72, ETV6, and DDX41, which are associated with familial myeloid malignancies...
June 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Jessica Lauriol, Janel R Cabrera, Ashbeel Roy, Kimberly Keith, Sara M Hough, Federico Damilano, Bonnie Wang, Gabriel C Segarra, Meaghan E Flessa, Lauren E Miller, Saumya Das, Roderick Bronson, Kyu-Ho Lee, Maria I Kontaridis
Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium...
August 1, 2016: Journal of Clinical Investigation
Magnhild Selås, Wenche Andersen Helland
Noonan syndrome (NS) is a disorder causing symptoms like short stature, characteristic facial features, congenital heart disease, possible mental retardation and pragmatic difficulties. This study describes the pragmatic skills in NS and discusses the linguistic profile of 17 informants aged 6-15 years, by comparing the participants' scores on the Children's Communication Checklist, 2nd Edition (CCC-2) (Bishop, 2011), with a group of typically developing children of matching age and gender. Language impairments were common in the NS group...
June 27, 2016: Clinical Linguistics & Phonetics
Boyang Zhao, Justin R Pritchard
The identification of biologically significant variants in cancer genomes is critical to therapeutic discovery, but it is limited by the statistical power needed to discern driver from passenger. Independent biological data can be used to filter cancer exomes and increase statistical power. Large genetic databases for inherited diseases are uniquely suited to this task because they contain specific amino acid alterations with known pathogenicity and molecular mechanisms. However, no rigorous method to overlay this information onto the cancer exome exists...
June 2016: PLoS Genetics
Zhenhao Fang, Christopher B Marshall, Jiani C Yin, Mohammad T Mazhab-Jafari, Geneviève M C Gasmi-Seabrook, Matthew J Smith, Tadateru Nishikawa, Yang Xu, Benjamin G Neel, Mitsuhiko Ikura
RAS-like protein expressed in many tissues 1 (RIT1) is a disease-associated RAS subfamily small guanosine triphosphatase (GTPase). Recent studies revealed that germ-line and somatic RIT1 mutations can cause Noonan syndrome (NS), and drive proliferation of lung adenocarcinomas, respectively, akin to RAS mutations in these diseases. However, the locations of these RIT1 mutations differ significantly from those found in RAS, and do not affect the three mutational "hot spots" of RAS. Moreover, few studies have characterized the GTPase cycle of RIT1 and its disease-associated mutants...
July 22, 2016: Journal of Biological Chemistry
Libertad Latorre Navarro, Luis García-Guereta Silva, Elena Ruíz Bravo-Burguillos
CLINICAL INTRODUCTION: A previously healthy 12-year-old boy presented with chest pain and dyspnoea. ECG (figure 1), echocardiogram (figure 2) and myocardial MRI (figure 3) were performed.Electromyography revealed mild proximal weakness. Blood tests showed creatine kinase 997 UI/L, aspartate transaminase 398 UI/L, alanine transaminase 293 UI/L and lactate deshidrogenase 1730 UI/L. Ophthalmology test showed diffuse loss of pigment in the retinal pigment epithelium. Myocardial biopsy was performed (figure 4)...
September 15, 2016: Heart: Official Journal of the British Cardiac Society
Tejas Patil, Dara L Aisner, Sinead A Noonan, Paul A Bunn, William T Purcell, Laurie L Carr, D Ross Camidge, Robert C Doebele
INTRODUCTION: Peritoneal metastasis from lung cancer is an uncommon clinical event and there are limited data on what factors predict peritoneal progression. This study retrospectively investigated whether patterns of metastatic spread and oncogene status in patients with advanced non-small cell lung cancer (NSCLC) are associated with peritoneal metastasis. METHODS: Patients with metastatic non-squamous NSCLC (n=410) were identified at the University of Colorado Cancer Center...
June 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Karim Kouz, Christina Lissewski, Stephanie Spranger, Diana Mitter, Angelika Riess, Vanesa Lopez-Gonzalez, Sabine Lüttgen, Hatip Aydin, Florian von Deimling, Christina Evers, Andreas Hahn, Maja Hempel, Ulrike Issa, Anne-Karin Kahlert, Adrian Lieb, Pablo Villavicencio-Lorini, Maria Juliana Ballesta-Martinez, Sheela Nampoothiri, Angela Ovens-Raeder, Alena Puchmajerová, Robin Satanovskij, Heide Seidel, Stephan Unkelbach, Bernhard Zabel, Kerstin Kutsche, Martin Zenker
PURPOSE: Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited. METHODS: We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS...
April 21, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Ivan Borrello, Kimberly A Noonan
The past several years have witnessed the acceptance of immunotherapy into the mainstream of therapies for patients with cancer. This has been driven by the clinical successes of antibodies to the checkpoint inhibitors, CTLA-4 and PD-1, capable of imparting long-term remissions in several solid tumors as well as Hodgkin's lymphoma (1) and the therapeutic successes of adoptive T-cell transfer with chimeric antigen receptors (2) or modified T-cell receptors (3) that have mostly utilized peripheral T-cells. One emerging area of therapeutic T cell intervention has been the utilization of marrow-infiltrating lymphocytes (MILs) - a novel form of adoptive T-cell therapy...
2016: Frontiers in Immunology
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