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https://www.readbyqxmd.com/read/28092822/combination-of-everolimus-with-sorafenib-for-solid-renal-tumors-in-tsc2-mice-is-superior-to-everolimus-alone
#1
Jian Yang, Paulina A Samsel, Kalin Narov, Ashley Jones, Daniel Gallacher, John Gallacher, Julian R Sampson, Ming Hong Shen
Tuberous sclerosis (TSC) is an inherited tumor syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumors in multiple organs including the kidneys. The mTOR inhibitors rapamycin and everolimus (rapalogs) have demonstrated clinical efficacy in treating TSC-associated tumors including renal angiomyolipomas. However, tumor responses are usually only partial, and regrowth occurs after drug withdrawal. TSC-associated tumors are highly vascular, and TSC patients with renal angiomyolipomas have elevated levels of circulating vascular endothelial growth factor (VEGF) A and VEGFD...
January 13, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28092373/chronic-signaling-via-the-metabolic-checkpoint-kinase-mtorc1-induces-macrophage-granuloma-formation-and-marks-sarcoidosis-progression
#2
Monika Linke, Ha Thi Thanh Pham, Karl Katholnig, Thomas Schnöller, Anne Miller, Florian Demel, Birgit Schütz, Margit Rosner, Boris Kovacic, Nyamdelger Sukhbaatar, Birgit Niederreiter, Stephan Blüml, Peter Kuess, Veronika Sexl, Mathias Müller, Mario Mikula, Wolfram Weckwerth, Arvand Haschemi, Martin Susani, Markus Hengstschläger, Michael J Gambello, Thomas Weichhart
The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo...
January 16, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28087349/combination-of-multiple-ligation-dependent-probe-amplification-and-illumina-miseq-amplicon-sequencing-for-tsc1-tsc2-gene-analyses-in-patients-with-tuberous-sclerosis-complex
#3
Nur Farrah Dila Ismail, Abdul Qawee Rani, Nik Mohd Ariff Nik Abdul Malik, Chia Boon Hock, Siti Nabilahuda Mohd Azlan, Salmi Abdul Razak, Wee Teik Keng, Lock Hock Ngu, Abdul Rashid Silawati, Nor AzniYahya, Narazah Mohd Yusoff, Teguh Haryo Sasongko, Zabidi Azhar Mohd Hussin
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by tumor growth in multiple organs and caused by mutations in either TSC1 or TSC2 genes. Because of their relatively large genomic sizes, absence of hotspots, and common type of mutations, mutation detection in TSC1 and TSC2 genes has been challenging. We devised a combination of multiple ligation-dependent probe amplification (MLPA) and amplicon sequencing (AS) to simplify the detection strategy, yet we come up with reasonably high detection rate...
January 10, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28076433/enhanced-rb-e2f-and-tsc-mtor-pathways-induce-synergistic-inhibition-in-pdgf-induced-proliferation-in-vascular-smooth-muscle-cells
#4
Yue Li, Xuan Li, Jie Liu, Wei Guo, Hongchao Zhang, Jianchang Wang
Platelet-derived growth factor (PDGF) plays an essential role in proliferation of vascular smooth muscle cells (VSMCs). The Rb/E2F and TSC/mTOR pathways contribute to the proliferation of VSMCs, but its exact roles in PDGF-induced proliferation are unclear. In this study, we demonstrated the roles of Rb/E2F and TSC/mTOR pathways in PDGF-induced proliferation in VSMCs. We found that PDGF stimulates the activity of E2F and mTOR pathways, and knockdown of either Rb or TSC2 increases PDGF-induced proliferation in VSMCs...
2017: PloS One
https://www.readbyqxmd.com/read/28074849/genetic-variants-identified-from-epilepsy-of-unknown-etiology-in-chinese-children-by-targeted-exome-sequencing
#5
Yimin Wang, Xiaonan Du, Rao Bin, Shanshan Yu, Zhezhi Xia, Guo Zheng, Jianmin Zhong, Yunjian Zhang, Yong-Hui Jiang, Yi Wang
Genetic factors play a major role in the etiology of epilepsy disorders. Recent genomics studies using next generation sequencing (NGS) technique have identified a large number of genetic variants including copy number (CNV) and single nucleotide variant (SNV) in a small set of genes from individuals with epilepsy. These discoveries have contributed significantly to evaluate the etiology of epilepsy in clinic and lay the foundation to develop molecular specific treatment. However, the molecular basis for a majority of epilepsy patients remains elusive, and furthermore, most of these studies have been conducted in Caucasian children...
January 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28065512/assessment-of-tuberous-sclerosis-complex-associated-with-renal-lesions-by-targeted-next-generation-sequencing-in-mainland-china
#6
Yi Cai, Hanzhong Li, Yushi Zhang
OBJECTIVE: To identify the TSC1 and TSC2 mutations in patients with tuberous sclerosis complex (TSC) associated with renal lesions, and to explore the relationship between genotypes and phenotypes. MATERIALS AND METHODS: We analyzed 43 individuals affected with TSC accompanied by renal lesions using next-generation sequencing (NGS). We also performed Sanger sequencing to validate the NGS results. RESULTS: We reported a comprehensive mutation analysis of 43 affected individuals with TSC accompanied by renal lesions using NGS...
January 5, 2017: Urology
https://www.readbyqxmd.com/read/28061838/cryptotanshinone-activates-ampk-tsc2-axis-leading-to-inhibition-of-mtorc1-signaling-in-cancer-cells
#7
Wenxing Chen, Yanhong Pan, Siliang Wang, Yuping Liu, Guangying Chen, Liang Zhou, Wenting Ni, Aiyun Wang, Yin Lu
BACKGROUND: Cryptotanshinone (CPT), a fat-soluble phenanthraquinone from Salvia miltiorrhiza Bunge, has been demonstrated to inhibit phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), a couple of direct downstream effectors of the mammalian target of rapamycin complex 1 (mTORC1), resulting in cancer cell arrested in G0 phase and subsequent inhibition of proliferation. However, its concrete molecular mechanism about how CPT inhibits mTORC1 signaling pathway is unclear...
January 7, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28053551/genetics-of-tuberous-sclerosis-complex-implications-for-clinical-practice
#8
REVIEW
Carolina Caban, Nubaira Khan, Daphne M Hasbani, Peter B Crino
Tuberous sclerosis complex (TSC) is a multisystem disorder that results from heterozygous mutations in either TSC1 or TSC2. The primary organ systems that are affected include the brain, skin, lung, kidney, and heart, all with variable frequency, penetrance, and severity. Neurological features include epilepsy, autism, and intellectual disability. There are more than 1,500 known pathogenic variants for TSC1 and TSC2, including deletion, nonsense, and missense mutations, and all pathogenic mutations are inactivating, leading to loss of function effects on the encoded proteins TSC1 and TSC2...
2017: Application of Clinical Genetics
https://www.readbyqxmd.com/read/28053105/epstein-barr-virus-encoded-latent-membrane-protein-1-upregulates-glucose-transporter-1-transcription-via-the-mtorc1-nf-%C3%AE%C2%BAb-signaling-pathways
#9
Jun Zhang, Lin Jia, Weitao Lin, Yim Ling Yip, Kwok Wai Lo, Victoria Ming Yi Lau, Dandan Zhu, Chi Man Tsang, Yuan Zhou, Wen Deng, Hong Lok Lung, Maria Li Lung, Lai Man Cheung, Sai Wah Tsao
: Accumulating evidence indicates that oncogenic viral protein exerts a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a trans-membrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-κB is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-κB signaling to mediate aerobic glycolysis...
January 4, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28041982/4-nonylphenol-induces-autophagy-and-attenuates-mtor-p70s6k-4ebp1-signaling-by-modulating-ampk-activation-in-sertoli-cells
#10
Peng Duan, Chunhui Hu, Chao Quan, Tingting Yu, Wenting Huang, Wei Chen, Sha Tang, Yuqin Shi, Francis L Martin, Kedi Yang
The estrogenic chemical 4-nonylphenol (NP) is known to impair testicular devolopment and spermatogenesis in rodents. The objective of this study was to explore the effects of NP on autophagy induction and AMPK-mTOR signaling pathway in Sertoli cells (SCs), which are the "nursemaid cells" for meiosis of spermatocytes. In this study we exposed 7-week-old male rats to NP by intra-peritoneal injection at 0, 20, 50 or 100mg/kg body weight/2days for 20 consecutive days. Our results showed that exposure to NP dose-dependently induces the formation of autophagosomes in SCs, increases the expression of Beclin-1, the conversion of LC3-I to LC3-II and the mRNA expression of Atg3, Atg5, Atg7 and Atg12 in testis, and these effects are concomitant with the activation of AMPK, and the suppression of TSC2-mTOR-p70S6K/4EBP1 signaling cascade in testis...
December 29, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/28041914/repression-of-tsc1-tsc2-mediated-by-mecp2-regulates-human-embryo-lung-fibroblast-cell-differentiation-and-proliferation
#11
Yuanyuan Wang, Chen Chen, Ziyu Deng, Erbao Bian, Cheng Huang, Ting Lei, Xiongwen Lv, Liping Liu, Jun Li
Pulmonary fibrosis (PF) is a severe inflammatory disease with limited effective treatments. It is known that the transdifferentiation of human embryo lung fibroblast (HELF) cells from pulmonary fibroblasts into myofibroblasts, contributes to the progression of pulmonary fibrogenesis. The tuberous sclerosis proteins TSC1 and TSC2 are two key signaling factors which can suppress cell growth and proliferation. However, the roles of TSC1 and TSC2 in lung fibroblast are unclear. Here, we developed a PF model with bleomycin (BLM) in mice and conducted several simulation experiments in HELF cells...
December 29, 2016: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28027327/mutational-profile-of-metastatic-breast-cancers-a-retrospective-analysis
#12
Celine Lefebvre, Thomas Bachelot, Thomas Filleron, Marion Pedrero, Mario Campone, Jean-Charles Soria, Christophe Massard, Christelle Lévy, Monica Arnedos, Magali Lacroix-Triki, Julie Garrabey, Yannick Boursin, Marc Deloger, Yu Fu, Frédéric Commo, Véronique Scott, Ludovic Lacroix, Maria Vittoria Dieci, Maud Kamal, Véronique Diéras, Anthony Gonçalves, Jean-Marc Ferrerro, Gilles Romieu, Laurence Vanlemmens, Marie-Ange Mouret Reynier, Jean-Christophe Théry, Fanny Le Du, Séverine Guiu, Florence Dalenc, Gilles Clapisson, Hervé Bonnefoi, Marta Jimenez, Christophe Le Tourneau, Fabrice André
BACKGROUND: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. METHODS AND FINDINGS: Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/28013293/deficient-tsc1-tsc2-complex-suppression-of-sox9-osteopontin-akt-signalling-cascade-constrains-tumour-growth-in-tuberous-sclerosis-complex
#13
Fuquan Jin, Keguo Jiang, Shuang Ji, Li Wang, Zhaofei Ni, Fuqiang Huang, Chunjia Li, Rongrong Chen, Hongbing Zhang, Zhongdong Hu, Xiaojun Zha
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder featured with multi-organ benign tumours. Disruption of TSC1/TSC2 complex suppression on mammalian/mechanistic target of rapamycin (mTOR) signalling causes TSC. Hyperactive mTOR-mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC-associated tumours. In this study, we demonstrated that osteopontin (OPN) was dramatically reduced by loss of TSC1/TSC2 complex in Tsc2-null mouse embryonic fibroblasts (MEFs), rat uterine leiomyoma-derived Tsc2-deficient cells, genetically modified mouse TSC models, and clinical samples...
December 23, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27994516/genes-involved-in-angiogenesis-and-mtor-pathways-are-frequently-mutated-in-asian-patients-with-pancreatic-neuroendocrine-tumors
#14
Wen-Chi Chou, Po-Han Lin, Yi-Chen Yeh, Yi-Ming Shyr, Wen-Liang Fang, Shin-E Wang, Chun-Yu Liu, Peter Mu-Hsin Chang, Ming-Han Chen, Yi-Ping Hung, Chung-Pin Li, Yee Chao, Ming-Huang Chen
Introduction: To address the issue of limited data on and inconsistent findings for genetic alterations in pancreatic neuroendocrine tumors (pNETs), we analyzed sequences of known pNET-associated genes for their impact on clinical outcomes in a Taiwanese cohort. Methods: Tissue samples from 40 patients with sporadic pNETs were sequenced using a customized sequencing panel that analyzed 43 genes with either an established or potential association with pNETs. Genetic mutations and clinical outcomes were analyzed for potential associations...
2016: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/27984090/rip3-antagonizes-a-tsc2-mediated-pro-survival-pathway-in-glioblastoma-cell-death
#15
Gregory Fettweis, Emmanuel Di Valentin, Laurent L'homme, Cédric Lassence, Franck Dequiedt, Marianne Fillet, Isabelle Coupienne, Jacques Piette
Glioblastomas are the deadliest type of brain cancer and are frequently associated with poor prognosis and a high degree of recurrence despite removal by surgical resection and treatment by chemo- and radio-therapy. Photodynamic therapy (PDT) is a treatment well known to induce mainly necrotic and apoptotic cell death in solid tumors. 5-Aminolevulinic acid (5-ALA)-based PDT was recently shown to sensitize human glioblastoma cells (LN-18) to a RIP3 (Receptor Interacting Protein 3)-dependent cell death which is counter-acted by activation of autophagy...
October 27, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27974549/tsc1-2-mutations-define-a-molecular-subset-of-hcc-with-aggressive-behaviour-and-treatment-implication
#16
Daniel W H Ho, Lo K Chan, Yung T Chiu, Iris M J Xu, Ronnie T P Poon, Tan T Cheung, Chung N Tang, Victor W L Tang, Irene L O Lo, Polly W Y Lam, Derek T W Yau, Miao X Li, Chun M Wong, Irene O L Ng
OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence...
December 14, 2016: Gut
https://www.readbyqxmd.com/read/27918305/tuberous-sclerosis-complex-inactivation-disrupts-melanogenesis-via-mtorc1-activation
#17
Juxiang Cao, Magdalena E Tyburczy, Joel Moss, Thomas N Darling, Hans R Widlund, David J Kwiatkowski
Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regulator of mTOR complex 1 (mTORC1). Patients with TSC develop hypomelanotic macules (white spots), but the molecular mechanisms underlying their formation are not fully characterized. Using human primary melanocytes and a highly pigmented melanoma cell line, we demonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activation, which results in hyperactivation of glycogen synthase kinase 3β (GSK3β), followed by phosphorylation of and loss of β-catenin from the nucleus, thereby reducing expression of microphthalmia-associated transcription factor (MITF), and subsequent reductions in tyrosinase and other genes required for melanogenesis...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27909410/mechanosensitive-molecular-networks-involved-in-transducing-resistance-exercise-signals-into-muscle-protein-accretion
#18
REVIEW
Emil Rindom, Kristian Vissing
Loss of skeletal muscle myofibrillar protein with disease and/or inactivity can severely deteriorate muscle strength and function. Strategies to counteract wasting of muscle myofibrillar protein are therefore desirable and invite for considerations on the potential superiority of specific modes of resistance exercise and/or the adequacy of low load resistance exercise regimens as well as underlying mechanisms. In this regard, delineation of the potentially mechanosensitive molecular mechanisms underlying muscle protein synthesis (MPS), may contribute to an understanding on how differentiated resistance exercise can transduce a mechanical signal into stimulation of muscle accretion...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27908730/mtor-activation-is-critical-for-betulin-treatment-in-renal-cell-carcinoma-cells
#19
Wenlong Cheng, Shiqi Ji, Haijian Zhang, Zhixing Han, Qingjun Liu, Jianwen Wang, Hao Ping
Betulin, a natural product isolated from the bark of the birch trees, exhibits multiple anticancer effects. Activation of mTOR signaling pathway has been found in numerous cancers, including renal cell carcinoma (RCC). Here, we attempted to study whether mTOR signaling was essential for betulin to treat RCC. Based on cell survival and colony formation assays, we found that mTOR hyperactive RCC cell line 786-O cells were more sensitive to betulin treatment compared with mTOR-inactive Caki-2 cells. Knockdown of TSC2 in Caki-2 cells had similar results to 786-O cells, and mTOR silencing in 786-O cells rescued the inhibitory effect of betulin, indicating that betulin inhibited RCC cell proliferation in an mTOR-dependent manner...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27907099/analysis-of-a-mouse-skin-model-of-tuberous-sclerosis-complex
#20
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
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