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https://www.readbyqxmd.com/read/28643795/the-genomic-landscape-of-tuberous-sclerosis-complex
#1
Katie R Martin, Wanding Zhou, Megan J Bowman, Juliann Shih, Kit Sing Au, Kristin E Dittenhafer-Reed, Kellie A Sisson, Julie Koeman, Daniel J Weisenberger, Sandra L Cottingham, Steven T DeRoos, Orrin Devinsky, Mary E Winn, Andrew D Cherniack, Hui Shen, Hope Northrup, Darcy A Krueger, Jeffrey P MacKeigan
Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist...
June 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28643793/genomic-rearrangements-in-sporadic-lymphangioleiomyomatosis-an-evolving-genetic-story
#2
Stephen J Murphy, Simone B Terra, Faye R Harris, Aqsa Nasir, Jesse S Voss, James B Smadbeck, Sarah H Johnson, Vishnu Serla, Jay H Ryu, Eunhee S Yi, Benjamin R Kipp, George Vasmatzis, Eva M Carmona
Sporadic lymphangioleiomyomatosis is a progressive pulmonary cystic disease resulting from the infiltration of smooth muscle-like lymphangioleiomyomatosis cells into the lung. The migratory/metastasizing properties of the lymphangioleiomyomatosis cell together with the presence of somatic mutations, primarily in the tuberous sclerosis complex gene (TSC2), lead many to consider this a low-grade malignancy. As malignant tumors characteristically accumulate somatic structural variations, which have not been well studied in sporadic lymphangioleiomyomatosis, we utilized mate pair sequencing to define structural variations within laser capture microdissected enriched lymphangioleiomyomatosis cell populations from five sporadic lymphangioleiomyomatosis patients...
June 23, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28637240/tfeb-activation-restores-migration-ability-to-tsc1-deficient-adult-neural-stem-progenitor-cells
#3
Alessandro Magini, Alice Polchi, Danila Di Meo, Giuseppina Mariucci, Krizia Sagini, Federico De Marco, Tommaso Cassano, Stefano Giovagnoli, Diego Dolcetta, Carla Emiliani
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs)...
June 14, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28630390/kavalactone-yangonin-induces-autophagy-and-sensitizes-bladder-cancer-cells-to-flavokawain-a-and-docetaxel-via-inhibition-of-the-mtor-pathway
#4
Liu Zhongbo, Ha U-Syn, Yu Ke, Wu Chunli, Yokoyama Noriko, Zi Xiaolin
Consumption of kava (Piper methysticum Forst) has been linked to reduced cancer risk in the South Pacific Islands. Kavalactones are major bioactive components in kava root extracts, which have recently demonstrated anti-cancer activities. However, molecular mechanisms of kavalactones' anti-cancer action remain largely unknown. We have identified two kavalactones, yangonin and 5' 6'-dehydrokawain, as potent inducers of autophagic cell death in bladder cancer cells. The effect of yangonin inducing autophagy is associated with increased expression of beclin and ATG5...
June 20, 2017: Journal of Biomedical Research
https://www.readbyqxmd.com/read/28626070/potential-susceptibility-loci-identified-for-renal-cell-carcinoma-by-targeting-obesity-related-genes
#5
Xiang Shu, Mark P Purdue, Yuanqing Ye, Huakang Tu, Christopher G Wood, Nizar M Tannir, Zhaoming Wang, Demetrius Albanes, Susan M Gapstur, Victoria L Stevens, Nathaniel Rothman, Stephen J Chanock, Xifeng Wu
BACKGROUND: Obesity is an established risk factor for renal cell carcinoma (RCC). Although genome-wide association studies (GWAS) of RCC have identified several susceptibility loci, additional variants might be missed due to the highly conservative selection. METHODS: We conducted a multiphase study utilizing three independent genome-wide scans at MD Anderson Cancer Center (MDA RCC GWAS and MDA RCC OncoArray) and National Cancer Institute (NCI RCC GWAS), which consisted of a total of 3,530 cases and 5,714 controls, to investigate genetic variations in obesity-related genes and RCC risk...
June 16, 2017: Cancer Epidemiology, Biomarkers & Prevention
https://www.readbyqxmd.com/read/28623545/analysis-of-genotypes-and-phenotypes-in-chinese-children-with-tuberous-sclerosis-complex
#6
Dayong Bai, Junyang Zhao, Li Li, Jun Gao, Xu Wang
Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with serious clinical presentations, an autosomal dominant genetic disorder involving multiple organs and systems. We retrospectively investigated the clinical manifestations and genotypes of 20 Chinese children with TSC to enable informed diagnostic and surveillance recommendations in China. A retrospective analysis of clinical manifestations in 20 children (7.00±5.30 years old) with TSC was conducted. A genetic testing of the genes TSC1 and TSC2 was performed in 14 children...
June 14, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28620021/correction-for-wolff-et-al-cell-type-dependent-regulation-of-mtorc1-by-redd1-and-the-tumor-suppressors-tsc1-tsc2-and-lkb1-in-response-to-hypoxia
#7
Nicholas C Wolff, Silvia Vega-Rubin-de-Celis, Xian-Jin Xie, Diego H Castrillon, Wareef Kabbani, James Brugarolas
No abstract text is available yet for this article.
July 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28611587/downregulation-of-microrna-193b-3p-promotes-autophagy-and-cell-survival-by-targeting-tsc1-mtor-signaling-in-nsc-34-cells
#8
ChunYu Li, YongPing Chen, XuePing Chen, QianQian Wei, Bei Cao, HuiFang Shang
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of upper and lower motor neurons. MicroRNAs (miRNAs) are reported to be closely related to the development of ALS. However, the precise functions of miRNAs in the pathogenesis of ALS remain largely unknown. In previous studies, we determined that miRNA-193b-3p was significantly downregulated in patients with sporadic ALS (sALS). Here, we observed that miRNA-193b-3p was downregulated in the SOD1(G93A) mouse model of ALS and promoted cell death in NSC-34 cells...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28588230/characterization-of-developmental-defects-in-the-forebrain-resulting-from-hyperactivated-mtor-signaling-by-integrative-analysis-of-transcriptomic-and-proteomic-data
#9
Jiheon Shin, Minhyung Kim, Hee-Jung Jung, Hye Lim Cha, Haeyoung Suh-Kim, Sanghyun Ahn, Jaehoon Jung, YounAh Kim, Yukyung Jun, Sanghyuk Lee, Daehee Hwang, Jaesang Kim
Hyperactivated mTOR signaling in the developing brain has been implicated in multiple forms of pathology including tuberous sclerosis complex (TSC). To date, various phenotypic defects such as cortical lamination irregularity, subependymal nodule formation, dysmorphic astrocyte differentiation and dendritic malformation have been described for patients and animal models. However, downstream networks affected in the developing brain by hyperactivated mTOR signaling have yet to be characterized. Here, we present an integrated analysis of transcriptomes and proteomes generated from wild-type and Tsc1/Emx1-Cre forebrains...
June 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28587396/identification-of-the-mirna-target-gene-regulatory-network-in-intracranial-aneurysm-based-on-microarray-expression-data
#10
Kezhen Wang, Xinmin Wang, Hongzhu Lv, Chengzhi Cui, Jiyong Leng, Kai Xu, Guosong Yu, Jianwei Chen, Peiyu Cong
Intracranial aneurysm (IA) remains one of the most devastating neurological conditions. However, the pathophysiology of IA formation and rupture still remains unclear. The purpose of the present study was to identify the crucial microRNA (miRNA/miR) and genes involved in IAs and elucidate the mechanisms underlying the development of IAs. In the present study, novel miRNA regulation activities in IAs were investigated through the integration of public gene expression data of miRNA and mRNA using the Gene Expression Omnibus database, combined with bioinformatics prediction...
June 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28584888/autism-spectrum-disorder-neuropathology-and-animal-models
#11
REVIEW
Merina Varghese, Neha Keshav, Sarah Jacot-Descombes, Tahia Warda, Bridget Wicinski, Dara L Dickstein, Hala Harony-Nicolas, Silvia De Rubeis, Elodie Drapeau, Joseph D Buxbaum, Patrick R Hof
Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each...
June 5, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28576630/ca-125-in-disease-progression-and-treatment-of-lymphangioleiomyomatosis
#12
Connie G Glasgow, Gustavo Pacheco-Rodriguez, Wendy K Steagall, Mary E Haughey, Patricia A Julien-Williams, Mario P Stylianou, Bernadette R Gochuico, Joel Moss
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women caused by proliferation of neoplastic-like LAM cells, with mutations in the TSC1/2 tumor suppressor genes. Based on case reports, CA-125 (an ovarian cancer biomarker) can be elevated in LAM patients. We hypothesized that elevated serum CA-125 levels seen in some LAM patients were due to LAM, not other malignancies, and might respond to sirolimus treatment. METHODS: Serum CA-125 levels were measured for 241 patients at each visit...
May 30, 2017: Chest
https://www.readbyqxmd.com/read/28561026/r2tp-prefoldin-like-component-ruvbl1-ruvbl2-directly-interacts-with-znhit2-to-regulate-assembly-of-u5-small-nuclear-ribonucleoprotein
#13
Philippe Cloutier, Christian Poitras, Mathieu Durand, Omid Hekmat, Émilie Fiola-Masson, Annie Bouchard, Denis Faubert, Benoit Chabot, Benoit Coulombe
The R2TP/Prefoldin-like (R2TP/PFDL) complex has emerged as a cochaperone complex involved in the assembly of a number of critical protein complexes including snoRNPs, nuclear RNA polymerases and PIKK-containing complexes. Here we report on the use of multiple target affinity purification coupled to mass spectrometry to identify two additional complexes that interact with R2TP/PFDL: the TSC1-TSC2 complex and the U5 small nuclear ribonucleoprotein (snRNP). The interaction between R2TP/PFDL and the U5 snRNP is mostly mediated by the previously uncharacterized factor ZNHIT2...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28550454/oncogenic-roles-of-the-pi3k-akt-mtor-axis
#14
Masahiro Aoki, Teruaki Fujishita
The PI3K/AKT/mTOR pathway is frequently activated in various human cancers and has been considered a promising therapeutic target. Many of the positive regulators of the PI3K/AKT/mTOR axis, including the catalytic (p110α) and regulatory (p85α), of class IA PI3K, AKT, RHEB, mTOR, and eIF4E, possess oncogenic potentials, as demonstrated by transformation assays in vitro and by genetically engineered mouse models in vivo. Genetic evidences also indicate their roles in malignancies induced by activation of the upstream oncoproteins including receptor tyrosine kinases and RAS and those induced by the loss of the negative regulators of the PI3K/AKT/mTOR pathway such as PTEN, TSC1/2, LKB1, and PIPP...
May 28, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28547571/clinical-presentations-and-molecular-studies-of-invasive-renal-epithelioid-angiomyolipoma
#15
Cheng-Keng Chuang, Hsin Chia Angela Lin, Han-Yu Tasi, Kun-Han Lee, Yuting Kao, Fukai Leo Chuang, Ying-Hsu Chang, Po-Hung Lin, Chung-Yi Liu, See-Tong Pang
PURPOSE: Epithelioid angiomyolipoma (EAML) is a rare variant of renal angiomyolipoma with malignant potential, and the cytogenetic and clinical behavior of EAML remains a challenging issue. METHODS: We retrospectively analyze the clinical courses of five EAML, the use of everolimus on metastatic EAML, and next-generation sequencing (NGS) and polymerase chain reaction (PCR) studies to investigate the gene mutation of TSC and the impact of PI3K/Akt/mTOR signaling pathway in metastatic EAML...
May 25, 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28532995/histological-subtypes-of-hepatocellular-carcinoma-are-related-to-gene-mutations-and-molecular-tumour-classification
#16
Julien Calderaro, Gabrielle Couchy, Sandrine Imbeaud, Giuliana Amaddeo, Eric Letouzé, Jean-Frédéric Blanc, Christophe Laurent, Yacine Hajji, Daniel Azoulay, Paulette Bioulac-Sage, Jean-Charles Nault, Jessica Zucman-Rossi
BACKGROUND AND AIMS: Our increasing understanding of hepatocellular carcinoma (HCC) biology holds promise for personalized care, however its translation into clinical practice requires a precise knowledge of its relationship to tumour phenotype. METHODS: We aimed at investigating molecular-phenotypic correlations in a large series of HCC. To this purpose, 343 surgically resected HCC were investigated by pathological review, immunohistochemistry, gene expression profiling and sequencing...
May 19, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28520214/mtorc1-inhibits-nf-%C3%AE%C2%BAb-nfatc1-signaling-and-prevents-osteoclast-precursor-differentiation-in-vitro-and-in-mice
#17
Yue Zhang, Song Xu, Kai Li, Kang Tan, Kangyan Liang, Jian Wang, Junhui Shen, Wenchong Zou, Le Hu, Daozhang Cai, Changhai Ding, Mangmang Li, Guozhi Xiao, Bin Liu, Anling Liu, Xiaochun Bai
The mechanistic target of rapamycin complex 1 (mTORC1) is a critical sensor for bone homeostasis and bone formation; however, the role of mTORC1 in osteoclast development and the underlying mechanisms have not yet been fully established. Here, we found that mTORC1 activity declined during osteoclast precursors differentiation in vitro and in vivo. We further targeted deletion of Raptor (mTORC1 key component) or Tsc1 (mTORC1 negative regulator) to constitutively inhibit or activate mTORC1 in osteoclast precursors (monocytes/macrophages), using LyzM-cre mice...
May 18, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28512249/p62-sqstm1-cooperates-with-hyperactive-mtorc1-to-regulate-glutathione-production-maintain-mitochondrial-integrity-and-promote-tumorigenesis
#18
Hilaire C Lam, Christian V Baglini, Alicia Llorente Lope, Andrey A Parkhitko, Heng-Jia Liu, Nicola Alesi, Izabela A Malinowska, Darius Ebrahimi-Fakhari, Afshin Saffari, Jane J Yu, Ana Pereira, Damir Khabibullin, Barbara Ogorek, Julie Nijmeh, Taylor Kavanagh, Adam Handen, Stephen Y Chan, John M Asara, William M Oldham, Maria T Diaz-Meco, Jorge Moscat, Mustafa Sahin, Carmen Priolo, Elizabeth P Henske
p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate that accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes tuberous sclerosis complex (TSC)1 or TSC2. Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2(+/-) and Tsc2f/f Ksp-CreERT2(+) mice crossed to p62(-/-) mice were protected from renal tumor development. Metabolic profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, glutamate, and glutathione (GSH)...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28498820/lysosomal-regulation-of-cholesterol-homeostasis-in-tuberous-sclerosis-complex-is-mediated-via-npc1-and-ldl-r
#19
Harilaos Filippakis, Nicola Alesi, Barbara Ogorek, Julie Nijmeh, Damir Khabibullin, Catherine Gutierrez, Alexander J Valvezan, James Cunningham, Carmen Priolo, Elizabeth P Henske
Tuberous sclerosis complex (TSC) is a multisystem disease associated with hyperactive mTORC1. The impact of TSC1/2 deficiency on lysosome-mediated processes is not fully understood. We report here that inhibition of lysosomal function using chloroquine (CQ) upregulates cholesterol homeostasis genes in TSC2-deficient cells. This TSC2-dependent transcriptional signature is associated with increased accumulation and intracellular levels of both total cholesterol and cholesterol esters. Unexpectedly, engaging this CQ-induced cholesterol uptake pathway together with inhibition of de novo cholesterol synthesis allows survival of TSC2-deficient, but not TSC2-expressing cells...
June 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28496353/early-manifestations-of-renal-disease-in-patients-with-tuberous-sclerosis-complex
#20
Laura Malaga-Dieguez, Robert Spencer, Laura J Pehrson, Suzanne Vento, Kimberly Menzer, Orrin Devinsky, Howard Trachtman
OBJECTIVES: Renal manifestations are the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC), and include renal cysts, angiomyolipomas, fat-poor lesions, and malignant tumors. These lesions begin in childhood and often lead to chronic kidney disease (CKD). Little is known on the incidence of early modifiable risk factors of CKD, such as proteinuria and hypertension, or subtle decreases in glomerular filtration rate that correspond to the early stages of CKD in children with TSC...
2017: International Journal of Nephrology and Renovascular Disease
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