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neurofibromin 1

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https://www.readbyqxmd.com/read/29673180/accurate-classification-of-nf1-gene-variants-in-84-italian-patients-with-neurofibromatosis-type-1
#1
Alessandro Stella, Patrizia Lastella, Daria Carmela Loconte, Nenad Bukvic, Dora Varvara, Margherita Patruno, Rosanna Bagnulo, Rosaura Lovaglio, Nicola Bartolomeo, Gabriella Serio, Nicoletta Resta
Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic diseases. It is caused by mutations in the NF1 gene encoding for the large protein, neurofibromin. Genetic testing of NF1 is cumbersome because 50% of cases are sporadic, and there are no mutation hot spots. In addition, the most recognizable NF1 clinical features—café-au-lait (CALs) spots and axillary and/or inguinal freckling—appear early in childhood but are rather non-specific. Thus, the identification of causative variants is extremely important for early diagnosis, especially in paediatric patients...
April 17, 2018: Genes
https://www.readbyqxmd.com/read/29670214/restoring-functional-neurofibromin-by-protein-transduction
#2
K Mellert, S Lechner, M Lüdeke, M Lamla, P Möller, R Kemkemer, K Scheffzek, D Kaufmann
In Neurofibromatosis 1 (NF1) germ line loss of function mutations result in reduction of cellular neurofibromin content (NF1+/-, NF1 haploinsufficiency). The Ras-GAP neurofibromin is a very large cytoplasmic protein (2818 AA, 319 kDa) involved in the RAS-MAPK pathway. Aside from regulation of proliferation, it is involved in mechanosensoric of cells. We investigated neurofibromin replacement in cultured human fibroblasts showing reduced amount of neurofibromin. Full length neurofibromin was produced recombinantly in insect cells and purified...
April 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29667529/emerging-therapeutic-targets-for-neurofibromatosis-type-1
#3
James A Walker, Meena Upadhyaya
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited tumor predisposition syndrome with an incidence of one in 3000-4000 individuals with no currently effective therapies. The NF1 gene on chromosome 17 encodes neurofibromin, which functions as a negative regulator of RAS. NF1 is a chronic multi-system disorder affecting many different tissues. Due to cell-specific complexities of RAS signaling, therapeutic approaches for NF1 will likely have to focus on a particular tissue and manifestation of the disease...
April 18, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29666462/tranilast-inhibits-the-expression-of-genes-related-to-epithelial-mesenchymal-transition-and-angiogenesis-in-neurofibromin-deficient-cells
#4
Ritsuko Harigai, Shigeki Sakai, Hiroyuki Nobusue, Chikako Hirose, Oltea Sampetrean, Noriaki Minami, Yukie Hata, Takashi Kasama, Takanori Hirose, Toshiki Takenouchi, Kenjiro Kosaki, Kazuo Kishi, Hideyuki Saya, Yoshimi Arima
Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas...
April 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29662612/exploiting-mitochondrial-and-metabolic-homeostasis-as-a-vulnerability-in-nf1-deficient-cells
#5
Robert J Allaway, Matthew D Wood, Sondra L Downey, Stephanie J Bouley, Nicole A Traphagen, Jason D Wells, Jaya Batra, Sir Norman Melancon, Carol Ringelberg, William Seibel, Nancy Ratner, Yolanda Sanchez
Neurofibromatosis type 1 is a disease caused by mutation of neurofibromin 1 ( NF1 ), loss of which results in hyperactive Ras signaling and a concomitant increase in cell proliferation and survival. Patients with neurofibromatosis type 1 frequently develop tumors such as plexiform neurofibromas and malignant peripheral nerve sheath tumors. Mutation of NF1 or loss of the NF1 protein is also observed in glioblastoma, lung adenocarcinoma, and ovarian cancer among other sporadic cancers. A therapy that selectively targets NF1 deficient tumors would substantially advance our ability to treat these malignancies...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29655575/crmp2-neurofibromin-interface-drives-nf1-related-pain
#6
Aubin Moutal, Li Sun, Xiaofang Yang, Wennan Li, Song Cai, Shizhen Luo, Rajesh Khanna
An understudied symptom of the genetic disorder Neurofibromatosis type 1 (NF1) is chronic idiopathic pain. We used targeted editing of Nf1 in rats to provide direct evidence of a causal relationship between neurofibromin, the protein product of the Nf1 gene, and pain responses. Our study data identified a protein-interaction network with collapsin response meditator protein 2 (CRMP2) as a node and neurofibromin, syntaxin 1A, and the N-type voltage-gated calcium (CaV2.2) channel as interaction edges. Neurofibromin uncouples CRMP2 from syntaxin 1A...
April 12, 2018: Neuroscience
https://www.readbyqxmd.com/read/29644913/possible-modifier-genes-in-the-variation-of-neurofibromatosis-type-1-clinical-phenotypes
#7
Parisa Sharafi, Sükriye Ayter
Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder worldwide, caused by mutations in the (NF1) gene. Although NF1 is a single-gene disorder with autosomal-dominant inheritance, its clinical expression is highly variable and unpredictable. NF1 patients have the highest known mutation rate among all human disorders, with no clear genotype-phenotype correlations. Therefore, variations in NF1 mutations may not correlate with the variations in clinical phenotype. Indeed, for the same mutation, some NF1 patients may develop severe clinical symptoms whereas others will develop a mild phenotype...
April 12, 2018: Journal of Neurogenetics
https://www.readbyqxmd.com/read/29643433/neurofibromin-knockdown-in-glioma-cell-lines-is-associated-with-changes-in-cytokine-and-chemokine-secretion-in-vitro
#8
Matthew D Wood, Joydeep Mukherjee, Russell O Pieper
The neurofibromin-1 tumor suppressor gene (NF1) is altered in approximately 20% of sporadic glioblastoma (GBM) cases. NF1 deficient GBM frequently shows a mesenchymal gene expression signature, suggesting a relationship between NF1 status and the tumor microenvironment. To identify changes in the production of secreted cytokines/chemokines in NF1 deficient glioma, we applied cytokine arrays to conditioned media from a panel of three GBM cell lines after siRNA-mediated NF1 knockdown. We identified increased secretion of platelet-derived growth factor AA (PDGF-AA), chitinase-3-like protein 1 (CHI3L1), interleukin-8 (IL-8), and endoglin (ENG) in different subsets of these cell lines...
April 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29600692/the-window-of-opportunities-for-targeted-therapy-in-brafwt-nraswt-kitwt-melanoma-biology-and-clinical-implications-of-fusion-proteins-and-other-mutations
#9
Marina Berger, Georg Richtig, Karl Kashofer, Ariane Aigelsreiter, Erika Richtig
Treatment options in advanced melanoma have been subject to a major change over the last years. The discovery of the oncogenic point mutation BRAFV600E and subsequently developed BRAF inhibitors had a major impact on patient's survival. Further important mutations have been found in the NRAS gene, although not yet druggable, and others involve c-kit in acral and mucosal melanoma. Imatinib was shown to achieve high response rates in c-kit mutated melanoma. Despite good response rates in these targeted therapies and introduction of immunotherapy, there are still patients left, who develop resistance upon therapy or patients without the option of targeted therapy...
March 29, 2018: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
https://www.readbyqxmd.com/read/29599344/racial-disparities-in-the-molecular-landscape-of-cancer
#10
Elisabeth I Heath, Filipa Lynce, Joanne Xiu, Angela Ellerbrock, Sandeep K Reddy, Elias Obeid, Stephen V Liu, Aliccia Bollig-Fischer, Duska Separovic, Ari Vanderwalde
BACKGROUND/AIM: African Americans (AA) have the highest incidence and mortality of any racial/ethnic group in the US for most cancer types. Heterogeneity in the molecular biology of cancer, as a contributing factor to this disparity, is poorly understood. To address this gap in knowledge, we explored the molecular landscape of colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and high-grade glioma (HGG) from 271 AA and 636 Caucasian (CC) cases. MATERIALS AND METHODS: DNA from formalin-fixed paraffin-embedded tumors was sequenced using next-generation sequencing...
April 2018: Anticancer Research
https://www.readbyqxmd.com/read/29590612/a-conserved-circadian-function-for-the-neurofibromatosis-1-gene
#11
Lei Bai, Yool Lee, Cynthia T Hsu, Julie A Williams, Daniel Cavanaugh, Xiangzhong Zheng, Carly Stein, Paula Haynes, Han Wang, David H Gutmann, Amita Sehgal
Loss of the Neurofibromatosis 1 (Nf1) protein, neurofibromin, in Drosophila disrupts circadian rhythms of locomotor activity without impairing central clock function, suggesting effects downstream of the clock. However, the relevant cellular mechanisms are not known. Leveraging the discovery of output circuits for locomotor rhythms, we dissected cellular actions of neurofibromin in recently identified substrates. Herein, we show that neurofibromin affects the levels and cycling of calcium in multiple circadian peptidergic neurons...
March 27, 2018: Cell Reports
https://www.readbyqxmd.com/read/29588580/a-functional-snp-upstream-of-the-adrb2-gene-is-associated-with-copd
#12
Jin-Xiu Li, Wei-Ping Fu, Jing Zhang, Xiao-Hua Zhang, Chang Sun, Lu-Ming Dai, Li Zhong, Li Yu, Ya-Ping Zhang
Background: Previous studies have suggested that β2 -adrenergic receptor ( ADRB2 ) is associated with COPD. However, the role of genetic polymorphisms in ADRB2 on COPD has not been evaluated yet. Methods: In this study, SNaPshot genotyping, luciferase assay, chromatin immunoprecipitation and real-time polymerase chain reaction were adopted to investigate the association between ADRB2 genetic polymorphisms and COPD, comprehensively. Results: One single nucleotide polymorphism (rs12654778), located upstream of ADRB2 , showed a significant association with COPD by the logistic regression analysis after adjusting for age, sex and smoking history ( p =0...
2018: International Journal of Chronic Obstructive Pulmonary Disease
https://www.readbyqxmd.com/read/29522274/neurofibromin-nf1-genetic-variant-structure-function-analyses-using-a-full-length-mouse-cdna
#13
Deeann Wallis, Kairong Li, Hui Lui, Ke Hu, Mei-Jan Chen, Jing Li, Jungsoon Kang, Shamik Das, Bruce R Korf, Robert A Kesterson
Neurofibromatosis type 1 (NF1; MIM# 613113) is caused by pathogenic variants or mutations in the NF1 gene that encodes neurofibromin. We describe here a new approach to determining the functional consequences of NF1 genetic variants. We established a heterologous cell culture expression system using a full-length mouse Nf1 cDNA (mNf1) and human cell lines. We demonstrate that the full-length murine cDNA produces a >250 kDa neurofibromin protein that is capable of modulating Ras signaling. We created mutant cDNAs representing NF1 patient variants with different clinically relevant phenotypes, and assessed their ability to produce mature neurofibromin and restore Nf1 activity in NF1-/- cells...
March 9, 2018: Human Mutation
https://www.readbyqxmd.com/read/29478615/neurofibromatosis-type-1
#14
Patrick J Cimino, David H Gutmann
The neurofibromatoses are a group of three heterogeneous disorders that include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. NF1 is the most common of these three conditions, and represents one of the most frequently diagnosed cancer predisposition disorders involving the nervous system. While NF1 primarily affects the central and peripheral nervous system, multisystem involvement is the rule, with dermatologic, cardiovascular, gastrointestinal, and orthopedic affectation often reported...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29471550/phenotype-genotype-correlation-in-children-with-neurofibromatosis-type-1
#15
Christophe Barrea, Sandrine Vaessen, Saskia Bulk, Julie Harvengt, Jean-Paul Misson
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an incidence of ∼1 in 4,000 live births. Neurofibromin, the gene product, is ubiquitously expressed at high levels in the nervous system and functions as a tumor suppressor. Haploinsufficiency of neurofibromin through mutation leads to an increased risk of developing benign and malignant tumors in affected individuals. Although NF1 has complete penetrance, it displays considerable inter- and intrafamilial variability in phenotypic expression which poses disease prediction and management problems...
February 22, 2018: Neuropediatrics
https://www.readbyqxmd.com/read/29385676/naturally-occurring-canine-melanoma-as-a-predictive-comparative-oncology-model-for-human-mucosal-and-other-triple-wild-type-melanomas
#16
REVIEW
Belen Hernandez, Hibret A Adissu, Bih-Rong Wei, Helen T Michael, Glenn Merlino, R Mark Simpson
Melanoma remains mostly an untreatable fatal disease despite advances in decoding cancer genomics and developing new therapeutic modalities. Progress in patient care would benefit from additional predictive models germane for human disease mechanisms, tumor heterogeneity, and therapeutic responses. Toward this aim, this review documents comparative aspects of human and naturally occurring canine melanomas. Clinical presentation, pathology, therapies, and genetic alterations are highlighted in the context of current basic and translational research in comparative oncology...
January 30, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29228356/dietary-intervention-rescues-myopathy-associated-with-neurofibromatosis-type-1
#17
Matthew A Summers, Thusitha Rupasinghe, Emily R Vasiljevski, Frances J Evesson, Kathy Mikulec, Lauren Peacock, Kate G R Quinlan, Sandra T Cooper, Ute Roessner, David A Stevenson, David G Little, Aaron Schindeler
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with complex symptomology. In addition to a predisposition to tumors, children with NF1 can present with reduced muscle mass, global muscle weakness, and impaired motor skills, which can have a significant impact on quality of life. Genetic mouse models have shown a lipid storage disease phenotype may underlie muscle weakness in NF1. Herein we confirm that biopsy specimens from six individuals with NF1 similarly manifest features of a lipid storage myopathy, with marked accumulation of intramyocellular lipid, fibrosis, and mononuclear cell infiltrates...
February 15, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29144820/pheochromocytoma-a-genetic-and-diagnostic-update
#18
Leilani B Mercado-Asis, Katherine I Wolf, Ivana Jochmanova, David Taïeb
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathologic studies are performed to prove, localize, treat, and monitor disease progression. Improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (<1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
January 2018: Endocrine Practice
https://www.readbyqxmd.com/read/29130106/molecular-alterations-of-the-nf2-gene-in-hepatocellular-carcinoma-and-intrahepatic-cholangiocarcinoma
#19
Ning Zhang, Zhang Zhao, Jiang Long, Hai Li, Bei Zhang, Guangyong Chen, Xiaojin Li, Tingxia Lv, Wei Zhang, Xiaojuan Ou, Anjian Xu, Jian Huang
Neurofibromatosis type 2 with mutations in the neurofibromin 2 (NF2) gene, encoding the Merlin protein, is an autosomal dominant disorder characterized by enhanced cancer predisposition, particularly tumors of the central nervous system. Recent animal studies indicate that disruption of NF2/Merlin function in oval cells, which are hepatic progenitor cells, may lead to the development of primary liver cancers including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its role in human primary liver cancer remains unclear...
December 2017: Oncology Reports
https://www.readbyqxmd.com/read/28972170/%C3%AE-1-integrin-dependent-rac-group-i-pak-signaling-mediates-yap-activation-of-yes-associated-protein-1-yap1-via-nf2-merlin
#20
Hiba Sabra, Molly Brunner, Vinay Mandati, Bernhard Wehrle-Haller, Dominique Lallemand, Anne-Sophie Ribba, Genevieve Chevalier, Philippe Guardiola, Marc R Block, Daniel Bouvard
Cell adhesion to the extracellular matrix or to surrounding cells plays a key role in cell proliferation and differentiation and is critical for proper tissue homeostasis. An important pathway in adhesion-dependent cell proliferation is the Hippo signaling cascade, which is coregulated by the transcription factors Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ). However, how cells integrate extracellular information at the molecular level to regulate YAP1's nuclear localization is still puzzling...
November 24, 2017: Journal of Biological Chemistry
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