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https://www.readbyqxmd.com/read/27913603/the-tumor-suppressor-flcn-mediates-an-alternate-mtor-pathway-to-regulate-browning-of-adipose-tissue
#1
Shogo Wada, Michael Neinast, Cholsoon Jang, Yasir H Ibrahim, Gina Lee, Apoorva Babu, Jian Li, Atsushi Hoshino, Glenn C Rowe, James Rhee, José A Martina, Rosa Puertollano, John Blenis, Michael Morley, Joseph A Baur, Patrick Seale, Zoltan Arany
Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program...
December 2, 2016: Genes & Development
https://www.readbyqxmd.com/read/27907099/analysis-of-a-mouse-skin-model-of-tuberous-sclerosis-complex
#2
Yanan Guo, John R Dreier, Juxiang Cao, Heng Du, Scott R Granter, David J Kwiatkowski
Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which patients develop several types of tumors, including facial angiofibroma, subungual fibroma, Shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis. It is due to inactivating mutations in TSC1 or TSC2. We sought to generate a mouse model of one or more of these tumor types by targeting deletion of the Tsc1 gene to fibroblasts using the Fsp-Cre allele. Mutant, Tsc1ccFsp-Cre+ mice survived a median of nearly a year, and developed tumors in multiple sites but did not develop angiomyolipoma or lymphangioleiomyomatosis...
2016: PloS One
https://www.readbyqxmd.com/read/27894621/glomerulocystic-kidney-presenting-as-a-unilateral-kidney-mass-in-a-newborn-with-tuberous-sclerosis-report-of-a-case-and-review-of-the-literature
#3
Miguel Rito, Rafael Adame Cabrera
Glomerular cysts are defined as a 2-3 times dilation of Bowman spaces and their presence in at least 5% of the glomeruli defines the kidneys as glomerulocystic (GCK). The association between cystic kidney disease and the tuberous sclerosis complex (TSC) is well known, but its presentation as a unilateral mass with glomerulocystic pattern is rare. We describe a case of an infant with a prenatal diagnosis of TSC, with a renal mass that was believed to be a renal tumor. A four-month-old infant with maternal history of TSC and prenatally diagnosed subependymal nodules and a right renal mass underwent nephrectomy...
November 18, 2016: Pathology, Research and Practice
https://www.readbyqxmd.com/read/27890237/mosaic-disorders-of-the-pi3k-pten-akt-tsc-mtorc1-signaling-pathway
#4
REVIEW
Neera Nathan, Kim M Keppler-Noreuil, Leslie G Biesecker, Joel Moss, Thomas N Darling
Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway cause segmental overgrowth, hamartomas, and malignant tumors. Mosaicism for activating mutations in AKT1 or PIK3CA cause Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. Postzygotic mutations in PTEN or TSC1/TSC2 cause mosaic forms of PTEN hamartoma tumor syndrome or tuberous sclerosis complex, respectively. Distinct features observed in these mosaic conditions in part reflect differences in embryological timing or tissue type harboring the mutant cells...
January 2017: Dermatologic Clinics
https://www.readbyqxmd.com/read/27878438/interdependence-of-clinical-factors-predicting-cognition-in-children-with-tuberous-sclerosis-complex
#5
I E Overwater, B J H Verhaar, H F Lingsma, G C B Bindels-de Heus, A M W van den Ouweland, M Nellist, L W Ten Hoopen, Y Elgersma, H A Moll, M C Y de Wit
Cognitive development in patients with tuberous sclerosis complex is highly variable. Predictors in the infant years would be valuable to counsel parents and to support development. The aim of this study was to confirm factors that have been reported to be independently correlated with cognitive development. 102 patients included in this study were treated at the ENCORE-TSC expertise center of the Erasmus Medical Center-Sophia Children's Hospital. Data from the first 24 months of life were used, including details on epilepsy, motor development and mutation status...
November 22, 2016: Journal of Neurology
https://www.readbyqxmd.com/read/27872925/new-dinuclear-ruthenium-arene-complexes-containing-thiosemicarbazone-ligands-synthesis-structure-and-cytotoxic-studies
#6
Wei Su, Zhaofeng Tang, Peiyuan Li, Gufeng Wang, Qi Xiao, Yuchun Li, Shan Huang, Yunqiong Gu, Zefeng Lai, Yuexing Zhang
A series of mononuclear ruthenium arene complexes with thiosemicarbazone (TSC) ligands (A-type, 1-8) and their corresponding di-nuclear analogues (B-type, 9-16) were synthesized and characterized by NMR, elemental analysis and HR-ESI-mass spectrometry. The molecular structures of 1, 2, 6, 9-11 and 13-16 were determined using single-crystal X-ray diffraction analysis. The Gibbs free energy of the two examples of the two types of complexes (1 and 9) and the bonding order in their single-crystals were studied using density functional theory (DFT) calculations...
November 22, 2016: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/27863419/tsc-loss-distorts-dna-replication-programme-and-sensitises-cells-to-genotoxic-stress
#7
Govind M Pai, Alexandra Zielinski, Dennis Koalick, Kristin Ludwig, Zhao-Qi Wang, Kerstin Borgmann, Helmut Pospiech, Ignacio Rubio
Tuberous Sclerosis (TSC) is characterized by exorbitant mTORC1 signalling and manifests as non-malignant, apoptosis-prone neoplasia. Previous reports have shown that TSC-/- cells are highly susceptible to mild, innocuous doses of genotoxic stress, which drive TSC-/- cells into apoptotic death. It has been argued that this hypersensitivity to stress derives from a metabolic/energetic shortfall in TSC-/- cells, but how metabolic dysregulation affects the DNA damage response and cell cycle alterations in TSC-/- cells exposed to genotoxic stress is not understood...
November 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27862655/mourning-dr-alfred-g-knudson-the-two-hit-hypothesis-tumor-suppressor-genes-and-the-tuberous-sclerosis-complex
#8
REVIEW
Okio Hino, Toshiyuki Kobayashi
On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson utilized an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor-predisposing syndrome...
November 11, 2016: Cancer Science
https://www.readbyqxmd.com/read/27860334/maintenance-therapy-with-everolimus-for-subependymal-giant-cell-astrocytoma-in-patients-with-tuberous-sclerosis-the-eminents-study
#9
Joanna Trelinska, Iwona Dachowska, Dobromila Baranska, Konrad Stawiski, Katarzyna Kotulska, Wojciech Fendler, Sergiusz Jozwiak, Wojciech Mlynarski
OBJECTIVE: One of the therapeutic options for patients with tuberous sclerosis (TCS) and subependymal giant cell astrocytoma (SEGA) is everolimus treatment once daily, every day, to attain trough concentrations of 5-15 ng/ml (standard treatment). The aim of this study was to evaluate the efficacy and safety of a reduced dose of everolimus (three times a week with a daily dose as in standard treatment-maintenance therapy) in a group of patients who were previously treated with standard dose for at least 12 months...
November 15, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27859028/phenotypic-and-genotypic-characterization-of-chinese-children-diagnosed-withtuberous-sclerosis-complex
#10
Guang Yang, ZeNing Shi, Yan Meng, XiuYu Shi, LingYu Pang, ShuFang Ma, MengNa Zhang, YanYan Wang, LiPing Zou
We investigated the clinical phenotypes and genetic mutations in Chinese children diagnosed with tuberous sclerosis complex (TSC). Sequencing of TSC1 and TSC2 genes was performed in 117 children with TSC and their parents. Association of TSC gene mutations with clinical manifestations was investigated. All gene mutations were heterozygous including in 16 patients (13.7%) with mutations in TSC1 gene and 101 patients (86.3%) with mutations in TSC2 gene. Among the 16 patients with TSC1 gene mutations, 15 different types of mutations were found, which included five novel mutations; all patients had skin manifestations and epilepsy...
November 8, 2016: Clinical Genetics
https://www.readbyqxmd.com/read/27845047/tuberous-sclerosis-complex-protein-1-expression-is-affected-by-vhl-gene-alterations-and-hif-1%C3%AE-production-in-sporadic-clear-cell-renal-cell-carcinoma
#11
Svetozar S Damjanovic, Bojana B Ilic, Bojana B Beleslin Cokic, Jadranka A Antic, Jovana Z Bankovic, Ivana T Milicevic, Gordana S Rodic, Dusan S Ilic, Vera N Todorovic, Nela Puskas, Cane D Tulic
Alterations in von Hippel-Lindau gene (VHL) do not determine deregulation of hypoxia-inducible factors (HIFs) in clear-cell renal carcinoma (ccRCC). Their effects on tuberous sclerosis proteins (TSC1/2) and heat shock protein 90 (Hsp90) expressions in sporadic ccRCC are unknown. Therefore, we analyze the impact of VHL alterations and HIF-α production on the expression of TSC proteins and Hsp90 in these tumors. Alterations in VHL gene region exhibited 37/47 (78.7%) tumors. Monoallelic inactivation (intragenic mutation or LOH) was found in 10 (21...
November 12, 2016: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/27837201/efficacy-and-safety-of-topical-sirolimus-therapy-for-facial-angiofibromas-in-the-tuberous-sclerosis-complex-a-randomized-clinical-trial
#12
Mari Wataya-Kaneda, Ayumi Nakamura, Mari Tanaka, Misa Hayashi, Shoji Matsumoto, Koji Yamamoto, Ichiro Katayama
Importance: Inhibitors of mammalian target of rapamycin complex 1, such as sirolimus, effectively target skin lesions in tuberous sclerosis complex (TSC). However, systemic treatment causes adverse effects, and topical sirolimus has shown promise in the treatment of facial angiofibromas. Objective: To evaluate the efficacy, safety, and optimal concentration of a topical sirolimus gel vs placebo for treatment of facial angiofibromas in TSC. Design, Setting, and Participants: A double-blind, placebo-controlled, parallel-group, dose-escalation, phase 2 randomized clinical trial using 3 sirolimus gel concentrations was performed at Osaka University Hospital, Osaka, Japan...
November 12, 2016: JAMA Dermatology
https://www.readbyqxmd.com/read/27827363/control-of-diabetic-hyperglycaemia-and-insulin-resistance-through-tsc22d4
#13
Bilgen Ekim Üstünel, Kilian Friedrich, Adriano Maida, Xiaoyue Wang, Anja Krones-Herzig, Oksana Seibert, Anke Sommerfeld, Allan Jones, Tjeerd P Sijmonsma, Carsten Sticht, Norbert Gretz, Thomas Fleming, Peter P Nawroth, Wolfgang Stremmel, Adam J Rose, Mauricio Berriel-Diaz, Matthias Blüher, Stephan Herzig
Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models...
November 9, 2016: Nature Communications
https://www.readbyqxmd.com/read/27815691/mtor-inhibitors-in-children-current-indications-and-future-directions-in-neurology
#14
REVIEW
Anna Jeong, Michael Wong
The mammalian/mechanistic target of rapamycin (mTOR) pathway is a key signaling pathway that has been implicated in genetic epilepsy syndromes, neurodegenerative diseases, and conditions associated with autism spectrum disorder and cognitive impairment. The mTOR pathway has become an exciting treatment target for these various disorders, with mTOR inhibitors such as rapamycin being studied for their potential therapeutic applications. In particular, tuberous sclerosis complex (TSC) is a genetic disorder resulting from overactivation of the mTOR pathway, and pharmacologic therapy with mTOR inhibitors has emerged as a viable treatment option for the systemic manifestations of the disease...
December 2016: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/27815402/long-term-treatment-of-epilepsy-with-everolimus-in-tuberous-sclerosis
#15
Darcy A Krueger, Angus A Wilfong, Maxwell Mays, Christina M Talley, Karen Agricola, Cindy Tudor, Jamie Capal, Katherine Holland-Bouley, David Neal Franz
OBJECTIVE: To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC). METHODS: Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency compared to baseline...
November 4, 2016: Neurology
https://www.readbyqxmd.com/read/27812765/-esped-survey-tsc-disease-in-children-and%C3%A2-adolescents-preliminary-results-from-a%C3%A2-german%C3%A2-epidemiological-survey
#16
Lilian Mann, Daniel Ebrahimi-Fakhari, Beate Heinrich, Marina Flotats-Bastardas, Ludwig Gortner, Alexander von Gontard, Justine Niemcyzk, Martin Poryo, Sascha Meyer
BACKGROUND: Tuberous sclerosis complex (TSC) disease is a rare genetic, multi-organ disorder characterized by the occurrence of multiple hamartoma. METHODS: In cooperation with ESPED, Germany, a prospective, epidemiological study was performed to assess the incidence of newly diagnosed TSC disease in patients ≤18 years in Germany. Moreover, the following parameters were assessed: 1. Age distribution at initial diagnosis; 2. Percentage of patients with in utero diagnosis of TSC; 3...
November 3, 2016: Wiener Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27809914/efficacy-and-safety-of-everolimus-in-children-with-tsc-associated-epilepsy-pilot-data-from-an-open-single-center-prospective-study
#17
Sharon Samueli, Klaus Abraham, Anastasia Dressler, Gudrun Gröppel, Angelika Mühlebner-Fahrngruber, Theresa Scholl, Gregor Kasprian, Franco Laccone, Martha Feucht
BACKGROUND: Epilepsy occurs in up to 90 % of all individuals with tuberous sclerosis complex (TSC). In 67 % disease onset is during childhood. In ≥ 50 % seizures are refractory to currently available treatment options. The mTOR-Inhibitor Everolimus (Votubia®) was approved for the treatment of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML) in Europe in 2011. It's anticonvulsive/antiepileptic properties are promising, but evidence is still limited. Study aim was to evaluate the efficacy and safety of Everolimus in children and adolescents with TSC-associated epilepsies...
November 3, 2016: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/27802134/from-the-stem-of-the-placental-tree-trophoblast-stem-cells-and-their-progeny
#18
REVIEW
Paulina Anna Latos, Myriam Hemberger
Trophoblast stem cells (TSCs) retain the capacity to self-renew indefinitely and harbour the potential to differentiate into all trophoblast subtypes of the placenta. Recent studies have shown how signalling cascades integrate with transcription factor circuits to govern the fine balance between TSC self-renewal and differentiation. In addition, breakthroughs in reprogramming strategies have enabled the generation of TSCs from fibroblasts, opening up exciting new avenues that may allow the isolation of this stem cell type from other species, notably humans...
October 15, 2016: Development
https://www.readbyqxmd.com/read/27797585/beneficial-effects-of-everolimus-on-autism-and-attention-deficit-hyperactivity-disorder-symptoms-in-a-group-of-patients-with-tuberous-sclerosis-complex
#19
Ayse Kilincaslan, Burcu Ece Kok, Pinar Tekturk, Cengiz Yalcinkaya, Cigdem Ozkara, Zuhal Yapici
OBJECTIVES: Such neuropsychiatric symptoms as autism spectrum disorders, attention-deficit/hyperactivity disorder (ADHD), intellectual disability, aggression, and epilepsy are very common in patients with tuberous sclerosis complex (TSC). Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a recent and effective treatment for TSC patients with giant cell astrocytomas and renal angiomyolipoma, and it has been shown to have a potential to reduce tumor volume. However, there is a paucity of studies on the effects of everolimus on neuropsychiatric symptoms...
October 31, 2016: Journal of Child and Adolescent Psychopharmacology
https://www.readbyqxmd.com/read/27797139/tuberous-sclerosis-complex-from-molecular-biology-to-novel-therapeutic-approaches
#20
REVIEW
Katarzyna Switon, Katarzyna Kotulska, Aleksandra Janusz-Kaminska, Justyna Zmorzynska, Jacek Jaworski
Tuberous sclerosis complex (TSC) is a rare multi-system disorder, primary manifestations of which are benign tumors and lesions in various organs of the body, including the brain. TSC patients often suffer from epilepsy, mental retardation, and autism spectrum disorder (ASD). Therefore, TSC serves as a model of epilepsy, ASD, and tumorigenesis. TSC is caused by the lack of functional Tsc1-Tsc2 complex, which serves as a major cellular inhibitor of mammalian Target of Rapamycin Complex 1 (mTORC1). mTORC1 is a kinase controlling most of anabolic processes in eukaryotic cells...
October 31, 2016: IUBMB Life
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