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https://www.readbyqxmd.com/read/28918392/cnvs-affecting-cancer-predisposing-genes-cpgs-detected-as-incidental-findings-in-routine-germline-diagnostic-chromosomal-microarray-cma-testing
#1
Josie Innes, Lisa Reali, Jill Clayton-Smith, Georgina Hall, Derek Hk Lim, George J Burghel, Kim French, Unzela Khan, Daniel Walker, Fiona Lalloo, D Gareth R Evans, Dominic McMullan, Eamonn R Maher, Emma R Woodward
BACKGROUND: Identification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results. METHODS: We investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility...
September 16, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28903387/hyperactivated-mtorc1-downregulation-of-foxo3a-pdgfr%C3%AE-akt-cascade-restrains-tuberous-sclerosis-complex-associated-tumor-development
#2
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
#3
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/28894028/mtorc1-regulates-both-general-autophagy-and-mitophagy-induction-after-oxidative-phosphorylation-uncoupling
#4
Alberto Bartolomé, Ana García-Aguilar, Shun-Ichiro Asahara, Yoshiaki Kido, Carlos Guillén, Utpal B Pajvani, Manuel Benito
The mechanistic target of rapamycin complex 1 (MTORC1) is a critical negative regulator of general autophagy. We hypothesized that MTORC1 may specifically regulate autophagic clearance of damaged mitochondria. To test this, we used cells lacking tuberous sclerosis complex 2 (TSC2 -/-), which show constitutive MTORC1 activation. TSC2 -/- cells show MTORC1-dependent impaired autophagic flux after chemical uncoupling of mitochondria, increased mitochondrial protein aging and accumulation of p62/SQSTM1 positive mitochondria...
September 11, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28892148/mtor-mutations-in-smith-kingsmore-syndrome-four-additional-patients-and-a-review
#5
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
#6
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
#7
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/28874882/glucosyltransferase-activity-of-clostridium-difficile-toxin-b-triggers-autophagy-mediated-cell-growth-arrest
#8
Ruina He, Jingyu Peng, Pengfei Yuan, Junjiao Yang, Xiaoji Wu, Yinan Wang, Wensheng Wei
Autophagy is a bulk cell-degradation process that occurs through the lysosomal machinery, and many reports have shown that it participates in microbial pathogenicity. However, the role of autophagy in Clostridium difficile infection (CDI), the leading cause of antibiotics-associated diarrhea, pseudomembranous colitis and even death in severe cases, is not clear. Here we report that the major virulent factor toxin B (TcdB) of Clostridium difficile elicits a strong autophagy response in host cells through its glucosyltransferase activity...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28860410/next-generation-sequencing-for-patients-with-sarcoma-a-single-center-experience
#9
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/28844862/vps34-acetylation-controls-its-lipid-kinase-activity-and-the-initiation-of-canonical-and-non-canonical-autophagy
#10
Hua Su, Fei Yang, Qiuting Wang, Qiuhong Shen, Jingtao Huang, Chao Peng, Yi Zhang, Wei Wan, Catherine C L Wong, Qiming Sun, Fudi Wang, Tianhua Zhou, Wei Liu
The class III phosphoinositide 3-kinase VPS34 plays a key role in the regulation of vesicular trafficking and macroautophagy. So far, we know little about the molecular mechanism of VPS34 activation besides its interaction with regulatory proteins to form complexes. Here, we report that VPS34 is specifically acetylated by the acetyltransferase p300, and p300-mediated acetylation represses VPS34 activity. Acetylation at K771 directly diminishes the affinity of VPS34 for its substrate PI, while acetylation at K29 hinders the VPS34-Beclin 1 core complex formation...
August 23, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28844017/assessment-of-response-of-kidney-tumors-to-rapamycin-and-atorvastatin-in-tsc1-mice
#11
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
#12
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/28827467/teaching-neuroimages-huge-carotid-artery-aneurysm-in-tsc2-pkd1-contiguous-gene-syndrome
#13
Bow Wang, Yi-Fang Tu, Yi-Shan Tsai
No abstract text is available yet for this article.
August 22, 2017: Neurology
https://www.readbyqxmd.com/read/28816269/-microrna-differential-expression-profile-in-tuberous-sclerosis-complex-cell-line-tsc2-mefs-and-normal-cell-line-tsc2-mefs
#14
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/28810331/-effect-of-tsc2-gene-expression-downregulation-by-lentivirus-induced-rna-interference-on-u937-cell-line-and-its-mechanism
#15
Z F Xu, H X Liu, Y H Tan, X H Chen, F G Ren, Y F Zhang, J M Chang, N Zhang, J J Hu, H W Wang
Objective: To investigate the effect of biology and mTOR pathway activity of down-regulated TSC2 gene expression on U937 leukemia cells. Methods: Gene expression was down-regulated by lentivirus induced RNA interference on TSC2 high expressed U937 cell line; the proliferation, apoptosis and differentiation were detected by CCK-8 assay, colony formation assay and flow cytometry; the gene expression level and protein kinase activity were detected by qRT-PCR and Western blot. Results: Down-regulated expression of TSC2 gene promoted U937 cell proliferation and colony formation ability (P<0...
July 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28808237/coding-and-small-non-coding-transcriptional-landscape-of-tuberous-sclerosis-complex-cortical-tubers-implications-for-pathophysiology-and-treatment
#16
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/28800130/mir-130a-upregulates-mtor-pathway-by-targeting-tsc1-and-is-transactivated-by-nf-%C3%AE%C2%BAb-in-high-grade-serous-ovarian-carcinoma
#17
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/28777148/new-mechanisms-of-mtor-pathway-activation-in-kit-mutant-malignant-gists
#18
Jerzy Lasota, Artur Kowalik, Anna Felisiak-Golabek, Sebastian Zięba, Zeng-Feng Wang, Markku Miettinen
A great majority of gastrointestinal stromal tumors (GISTs) are primarily driven by gain-of-function KIT receptor tyrosine kinase mutations that subsequently lead to activation of phosphatidiylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway, a downstream effector of KIT signaling. KIT tyrosine kinase inhibitor, imatinib mesylate, has been successfully used for the treatment of primary, advanced, and disseminated GISTs. Recently, activation of mTOR pathway independent of KIT signaling was demonstrated in imatinib mesylate naïve malignant GISTs and treatment-resistant metastatic tumors...
August 2, 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/28771801/tuberous-sclerosis-complex-in-29-children-clinical-and-genetic-analysis-and-facial-angiofibroma-responses-to-topical-sirolimus
#19
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
#20
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)
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