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https://www.readbyqxmd.com/read/28903387/hyperactivated-mtorc1-downregulation-of-foxo3a-pdgfr%C3%AE-akt-cascade-restrains-tuberous-sclerosis-complex-associated-tumor-development
#1
Li Wang, Zhaofei Ni, Yujie Liu, Shuang Ji, Fuquan Jin, Keguo Jiang, Junfang Ma, Cuiping Ren, Hongbing Zhang, Zhongdong Hu, Xiaojun Zha
Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss-of-function mutations in either the TSC1 or TSC2 gene, leads to the development of tuberous sclerosis complex (TSC), a benign tumor syndrome with multiple affected organs. mTORC1-mediated inhibition of AKT constrains the tumor progression of TSC, but the exact mechanisms remain unclear. Herein we showed that loss of TSC1 or TSC2 downregulation of platelet-derived growth factor receptor α (PDGFRα) expression was mediated by mTORC1...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28895704/-novel-mutation-in-tsc2-gene-in-pediatric-patient-with-clinical-diagnosis-of-tuberous-sclerosis
#2
Gabriela Caicedo-Herrera, Estephania Candelo, Harry Pachajoa
Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal dominant disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. Clinical features are highly variable and could be developing over the life. We present a case of TSC with a molecular test that identified a novel variant in TSC2 gene. It is a sporadic missense mutation which has not been previously reported in the literature. It is caused by premature termination of protein translation and results in the production of truncated and non-functional proteins...
October 1, 2017: Archivos Argentinos de Pediatría
https://www.readbyqxmd.com/read/28892148/mtor-mutations-in-smith-kingsmore-syndrome-four-additional-patients-and-a-review
#3
G Gordo, J Tenorio, P Arias, F Santos-Simarro, S García-Miñaur, J C Moreno, J Nevado, E Vallespin, L Rodriguez-Laguna, R de Mena, I Dapia, M Palomares, Á Del Pozo, K Ibañez, J C Silla, E Barroso, V L Ruiz Pérez, V Martinez-Glez, P Lapunzina
Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA: 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis...
September 11, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28888969/mtor-related-neuropathology-in-mutant-tsc2-zebrafish-phenotypic-transcriptomic-and-pharmacological-analysis
#4
Chloë Scheldeman, James D Mills, Aleksandra Siekierska, Ines Serra, Daniëlle Copmans, Anand M Iyer, Benjamin J Whalley, Jan Maes, Anna C Jansen, Lieven Lagae, Eleonora Aronica, Peter A M de Witte
Tuberous sclerosis complex (TSC) is a rare, genetic disease caused by loss-of-function mutations in either TSC1 or TSC2. Patients with TSC are neurologically characterized by the presence of abnormal brain structure, intractable epilepsy and TSC-associated neuropsychiatric disorders. Given the lack of effective long-term treatments for TSC, there is a need to gain greater insight into TSC-related pathophysiology and to identify and develop new treatments. In this work we show that homozygous tsc2(-/-) mutant zebrafish larvae, but not tsc2(+/-) and WT larvae, display enlarged brains, reduced locomotor behavior and epileptiform discharges at 7dpf...
September 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28887784/pancreatic-neuroendocrine-tumor-in-a-patient-with-a-tsc1-variant-case-report-and-review-of-the-literature
#5
REVIEW
Parisa Mortaji, Katherine T Morris, Von Samedi, Steven Eberhardt, Shawnia Ryan
The majority of pancreatic neuroendocrine tumors (PNETs) are sporadic while 10-15% are attributable to one of several familial cancer syndromes. Hereditary forms are more commonly associated with Multiple Endocrine Neoplasia Type I and von Hippel Lindau Syndrome. However, patients with Tuberous sclerosis complex also have an increased incidence of PNETs. More often this has been reported in patients with TSC2 variants. In this case report, we summarize the literature regarding PNETs associated with Tuberous sclerosis complex, as well as present a case of a patient with a TSC1 variant and a PNET...
September 8, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28880149/dual-function-of-the-pi3k-akt-mtorc1-axis-in-myelination-of-the-peripheral-nervous-system
#6
Gianluca Figlia, Camilla Norrmén, Jorge A Pereira, Daniel Gerber, Ueli Suter
Myelination is a biosynthetically demanding process in which mTORC1, the gatekeeper of anabolism, occupies a privileged regulatory position. We have shown previously that loss of mTORC1 function in Schwann cells (SCs) hampers myelination. Here, we genetically disrupted key inhibitory components upstream of mTORC1, TSC1 or PTEN, in mouse SC development, adult homeostasis, and nerve injury. Surprisingly, the resulting mTORC1 hyperactivity led to markedly delayed onset of both developmental myelination and remyelination after injury...
September 7, 2017: ELife
https://www.readbyqxmd.com/read/28860410/next-generation-sequencing-for-patients-with-sarcoma-a-single-center-experience
#7
Gregory M Cote, Jie He, Edwin Choy
BACKGROUND: Sarcomas comprise over 50 subtypes of mesenchymal cancers. For the majority of sarcomas, the driver mutations remain unknown. In this article, we describe our experience with a targeted next-generation sequencing (NGS) platform in clinic patients. MATERIALS AND METHODS: We retrospectively analyzed results of NGS using 133 tumor samples from patients diagnosed with a variety of sarcomas that were analyzed with targeted NGS covering over 400 cancer-related genes (405 DNA, 265 RNA) on a commercially available platform...
August 31, 2017: Oncologist
https://www.readbyqxmd.com/read/28844017/assessment-of-response-of-kidney-tumors-to-rapamycin-and-atorvastatin-in-tsc1-mice
#8
Ming Hong Shen, Paulina Samsel, Louise L Shen, Kalin Narov, Jian Yang, Julian R Sampson
Atorvastatin is widely used to lower blood cholesterol and to reduce risk of cardiovascular disease-associated complications. Epidemiological investigations and preclinical studies suggest that statins such as atorvastatin have antitumor activity for various types of cancer. Tuberous sclerosis (TSC) is a tumor syndrome caused by TSC1 or TSC2 mutations that lead to aberrant activation of mTOR and tumor formation in multiple organs. Previous studies have demonstrated that atorvastatin selectively suppressed growth and proliferation of mouse Tsc2 null embryonic fibroblasts through inhibition of mTOR...
August 24, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28830860/human%C3%A2-pluripotent-stem-cell-derived-tsc2-haploinsufficient-smooth-muscle-cells-recapitulate%C3%A2-features-of-lymphangioleiomyomatosis
#9
Lisa M Julian, Sean P Delaney, Ying Wang, Alexander A Goldberg, Carole Doré, Julien Yockell-Lelièvre, Roger Y Tam, Krinio Giannikou, Fiona McMurray, Molly S Shoichet, Mary-Ellen Harper, Elizabeth P Henske, David J Kwiatkowski, Thomas N Darling, Joel Moss, Arnold S Kristof, William L Stanford
Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both Tuberous Sclerosis Complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSCs), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation...
August 22, 2017: Cancer Research
https://www.readbyqxmd.com/read/28829945/cycd-cdk4-and-discontinuities-in-dpp-signaling-activate-torc1-in-the-drosophila-wing-disc
#10
Jesús Romero-Pozuelo, Constantinos Demetriades, Phillip Schroeder, Aurelio A Teleman
The molecular mechanisms regulating animal tissue size during development are unclear. This question has been extensively studied in the Drosophila wing disc. Although cell growth is regulated by the kinase TORC1, no readout exists to visualize TORC1 activity in situ in Drosophila. Both the cell cycle and the morphogen Dpp are linked to tissue growth, but whether they regulate TORC1 activity is not known. We develop here an anti-phospho-dRpS6 antibody that detects TORC1 activity in situ. We find, unexpectedly, that TORC1 activity in the wing disc is patchy...
August 21, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28816269/-microrna-differential-expression-profile-in-tuberous-sclerosis-complex-cell-line-tsc2-mefs-and-normal-cell-line-tsc2-mefs
#11
Y Cai, H Guo, H Z Li, W D Wang, Y S Zhang
OBJECTIVE: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes, but the molecular events contributing to TSC are not well understood. However, little is known about the role of microRNAs in TSC. To explore the microRNA differential expression profile between tuberous sclerosis complex cell line TSC2(-/-) MEFs and normal type cell line TSC2(+/+) MEFs, and to provide new clues to study the mechanism of microRNA function in tuberous sclerosis complex...
August 18, 2017: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
https://www.readbyqxmd.com/read/28808237/coding-and-small-non-coding-transcriptional-landscape-of-tuberous-sclerosis-complex-cortical-tubers-implications-for-pathophysiology-and-treatment
#12
James D Mills, Anand M Iyer, Jackelien van Scheppingen, Anika Bongaarts, Jasper J Anink, Bart Janssen, Till S Zimmer, Wim G Spliet, Peter C van Rijen, Floor E Jansen, Martha Feucht, Johannes A Hainfellner, Pavel Krsek, Josef Zamecnik, Katarzyna Kotulska, Sergiusz Jozwiak, Anna Jansen, Lieven Lagae, Paolo Curatolo, David J Kwiatkowski, R Jeroen Pasterkamp, Ketharini Senthilkumar, Lars von Oerthel, Marco F Hoekman, Jan A Gorter, Peter B Crino, Angelika Mühlebner, Brendon P Scicluna, Eleonora Aronica
Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28802642/prognostic-value-of-tert-alterations-mutational-and-copy-number-alterations-burden-in-urothelial-carcinoma
#13
Sumit Isharwal, François Audenet, Esther Drill, Eugene J Pietzak, Gopa Iyer, Irina Ostrovnaya, Eugene Cha, Timothy Donahue, Maria Arcila, Gowtham Jayakumaran, Michael F Berger, Jonathan E Rosenberg, Dean F Bajorin, Jonathan Coleman, Guido Dalbagni, Victor E Reuter, Bernard H Bochner, David B Solit, Hikmat A Al-Ahmadie
Missense mutations in the TERT gene promoter occur at high frequency in multiple cancers, including urothelial carcinoma (UC). However, the relationship between TERT promoter mutations and UC patient outcomes is unclear due to conflicting reports in the literature. In this study, we examined the association of TERT alterations, tumor mutational burden per megabase (Mb), and copy number alteration (CNA) burden with clinical parameters and their prognostic value in a cohort of 398 urothelial tumors. The majority of TERT mutations were located at two promoter region hotspots (chromosome 5, 1 295 228 C>T and 1 295 250 C>T)...
August 10, 2017: European Urology Focus
https://www.readbyqxmd.com/read/28800130/mir-130a-upregulates-mtor-pathway-by-targeting-tsc1-and-is-transactivated-by-nf-%C3%AE%C2%BAb-in-high-grade-serous-ovarian-carcinoma
#14
Yuqiong Wang, Xiyu Zhang, Wei Tang, Zhenghong Lin, Limei Xu, Ruifen Dong, Yinuo Li, Jieyin Li, Zaixin Zhang, Xiangzhi Li, Ling Zhao, Jian-Jun Wei, Changshun Shao, Beihua Kong, Zhaojian Liu
Activation of mammalian target of rapamycin (mTOR) signaling pathway is associated with poor prognosis of epithelial ovarian cancer. The TSC1-TSC2 complex is a critical negative regulator of mTOR signaling. Here, we demonstrated that TSC1 was frequently downregulated in high-grade serous ovarian carcinoma (HGSOC) and low TSC1 expression level is associated with advanced tumor stage. We next identified miR-130a to be a negative regulator of TSC1 by targeting its 3'UTR. miR-130a was overexpressed in HGSOC and could drive proliferation and invasion/metastasis of ovarian cancer cells...
August 11, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28771801/tuberous-sclerosis-complex-in-29-children-clinical-and-genetic-analysis-and-facial-angiofibroma-responses-to-topical-sirolimus
#15
Senfen Wang, Yuanxiang Liu, Jinghai Wei, Jian Zhang, Zhaoyang Wang, Zigang Xu
BACKGROUND/OBJECTIVES: Tuberous sclerosis complex (TSC) is a genetic disorder and facial angiofibromas are disfiguring facial lesions. The aim of this study was to analyze the clinical and genetic features of TSC and to assess the treatment of facial angiofibromas using topical sirolimus in Chinese children. METHODS: Information was collected on 29 patients with TSC. Genetic analyses were performed in 12 children and their parents. Children were treated with 0.1% sirolimus ointment for 36 weeks...
September 2017: Pediatric Dermatology
https://www.readbyqxmd.com/read/28762286/childhood-onset-epileptic-encephalopathy-associated-with-isolated-focal-cortical-dysplasia-and-a-novel-tsc1-germline-mutation
#16
Hannes Hoelz, Eva Coppenrath, Konstanze Hoertnagel, Timo Roser, Moritz Tacke, Lucia Gerstl, Ingo Borggraefe
Tuberous sclerosis complex (TSC) is an autosomal-dominant inheritable neurocutaneous disease due to mutations within the TSC1 and TSC2 genes. Many patients present with West syndrome, a severe epilepsy syndrome characterized by the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia (continuous slow activity with an amplitude higher than 300 µV and multiregional spikes/polyspikes/sharp waves) and developmental regression. In this study, we report on a previously healthy patient with positive family history of epilepsy with new-onset epileptic encephalopathy at the age of 9 years...
March 1, 2017: Clinical EEG and Neuroscience: Official Journal of the EEG and Clinical Neuroscience Society (ENCS)
https://www.readbyqxmd.com/read/28760909/-span-style-font-weight-400-circulating-tumor-dna-reveals-clinically-actionable-somatic-genome-of-metastatic-bladder-cancer-span
#17
Gillian R Vandekerkhove, Tilman Todenhöfer, Matti Annala, Werner J Struss, Amanda Wong, Kevin Beja, Elie Ritch, Sonal Brahmbhatt, Stas Volik, Jörg Hennenlotter, Matti Nykter, Kim N Chi, Scott North, Arnulf Stenzl, Colin C Collins, Bernhard J Eigl, Peter C Black, Alexander W Wyatt
Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer (BCa), but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally-invasive tool to profile the tumor genome in real-time, but is critically under-explored in BCa. <p>Experimental Design: We applied a combination of whole exome sequencing and targeted sequencing across 50 BCa driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive BCa, including 37 with metastatic disease...
July 31, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28746872/aberrant-proteostasis-of-bmal1%C3%A2-underlies-circadian-abnormalities-in-a-paradigmatic-mtor-opathy
#18
Jonathan O Lipton, Lara M Boyle, Elizabeth D Yuan, Kevin J Hochstrasser, Fortunate F Chifamba, Ashwin Nathan, Peter T Tsai, Fred Davis, Mustafa Sahin
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28737457/-importance-of-gross-deletions-in-the-diagnosis-of-tuberous-sclerosis-complex-the-first-hungarian-cases
#19
Erzsébet Kövesdi, Judit Bene, Nikoletta Nagy, Ágnes Horváth, Béla Melegh, Kinga Hadzsiev
Tuberous sclerosis complex is a rare disease with high phenotypic heterogeneity, characterized by the appearance of multiplex hamartomas in the different organs. The disease is inherited by autosomal dominant manner, due to the mutations of two genes: the TSC1 or the TSC2. In this publication we present the cases of two young male and two middle-aged female patients, where pathogenetic differences of TSC1/TSC2 could not be verified by Sanger sequencing. However, multiplex ligation-dependent probe amplification confirmed different sizes of deletions in different regions of the TSC2 gene...
July 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28712664/gsk3-and-its-interactions-with-the-pi3k-akt-mtor-signalling-network
#20
REVIEW
Miguel A Hermida, J Dinesh Kumar, Nick R Leslie
Glycogen Synthase Kinase-3 (GSK3 or GSK-3) is a promiscuous protein kinase and its phosphorylation of its diverse substrates has major influences on many areas of physiology and pathology, including cellular metabolism, lineage commitment and neuroscience. GSK3 was one of the first identified substrates of the heavily studied oncogenic kinase AKT, phosphorylation by which inhibits GSK3 activity via the formation of an autoinhibitory pseudosubstrate sequence. This has led to investigation of the role of GSK3 inhibition as a key component of the cellular responses to growth factors and insulin, which stimulate the class I PI 3-Kinases and in turn AKT activity and GSK3 phosphorylation...
June 27, 2017: Advances in Biological Regulation
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