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https://www.readbyqxmd.com/read/29782307/cutaneous-manifestations-of-tuberous-sclerosis
#1
Mirjana Bakić, Marina Ratković, Branka Gledović, Balsa Vujović, Danilo Radunović, Vera Babić, Vladimir Prelević
Dear Editor, Tuberous sclerosis (TS) is an autosomal dominant multisystem disease, which occurs due to genetically determined hyperplasia of ectodermal and mesodermal cells. Clinical manifestations present on the skin and in the nervous system, kidneys, heart, and other organs. Recent studies estimate the incidence of TS at 1/6000 to 1/10,000 live births, and a prevalence in the general population of approximately 1 in 20,000 (1). There are two different genetic loci responsible for TS: 9q34 (TSC1-hamartin) and 16p13...
April 2018: Acta Dermatovenerologica Croatica: ADC
https://www.readbyqxmd.com/read/29774133/sporadic-renal-angiomyolipoma-in-a-patient-with-birt-hogg-dub%C3%A3-chaperones-in-pathogenesis
#2
Rebecca A Sager, Mark R Woodford, Oleg Shapiro, Mehdi Mollapour, Gennady Bratslavsky
Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29766046/deletion-of-tsc2-in-nociceptors-reduces-target-innervation-ion-channel-expression-and-sensitivity-to-heat
#3
Dan Carlin, Judith P Golden, Amit Mogha, Vijay K Samineni, Kelly R Monk, Robert W Gereau, Valeria Cavalli
The mechanistic target of rapamycin complex 1 (mTORC1) is known to regulate cellular growth pathways, and its genetic activation is sufficient to enhance regenerative axon growth following injury to the central or peripheral nervous systems. However, excess mTORC1 activation may promote innervation defects, and mTORC1 activity mediates injury-induced hypersensitivity, reducing enthusiasm for the pathway as a therapeutic target. While mTORC1 activity is required for full expression of some pain modalities, the effects of pathway activation on nociceptor phenotypes and sensory behaviors are currently unknown...
March 2018: ENeuro
https://www.readbyqxmd.com/read/29764404/advanced-sporadic-renal-epithelioid-angiomyolipoma-case-report-of-an-extraordinary-response-to-sirolimus-linked-to-tsc2-mutation
#4
Marta Espinosa, Juan Maria Roldán-Romero, Ignacio Duran, Enrique de Álava, María Apellaniz-Ruiz, Alberto Cascón, Carmen Garrigos, Mercedes Robledo, Cristina Rodriguez-Antona
BACKGROUND: Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined. CASE PRESENTATION: Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae...
May 15, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29758070/rapamycin-independent-igf2-expression-in-tsc2-null-mouse-embryo-fibroblasts-and-human-lymphangioleiomyomatosis-cells
#5
Blanca E Himes, Kseniya Obraztsova, Lurong Lian, Maya Shumyatcher, Ryan Rue, Elena N Atochina-Vasserman, Stella K Hur, Marisa S Bartolomei, Jilly F Evans, Vera P Krymskaya
Lymphangioleiomyomatosis (LAM) is a rare, almost exclusively female lung disease linked to inactivating mutations in tuberous sclerosis complex 2 (TSC2), a tumor suppressor gene that controls cell metabolic state and growth via regulation of the mechanistic target of rapamycin (mTORC1) signaling. mTORC1 is frequently activated in human cancers and, although the mTORC1 inhibitor rapamycin has a cytostatic effect, it is, in general, unable to elicit a robust curative effect or tumor regression. Using RNA-Seq, we identified (1) Insulin-like Growth Factor (IGF2) as one of the genes with the highest fold-change difference between human TSC2-null and TSC2-expressing angiomyolipoma cells from a patient with LAM, and (2) the mouse IGF2 homolog Igf2, as a top-ranking gene according to fold change between Tsc2-/- and Tsc2+/+ mouse embryo fibroblasts (MEFs)...
2018: PloS One
https://www.readbyqxmd.com/read/29750810/mtor-signaling-regulates-central-and-peripheral-circadian-clock-function
#6
Chidambaram Ramanathan, Nimish D Kathale, Dong Liu, Choogon Lee, David A Freeman, John B Hogenesch, Ruifeng Cao, Andrew C Liu
The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators...
May 11, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29740858/novel-mutations-in-chinese-han-patients-with-tuberous-sclerosis-complex-case-series-and-review-of-the-published-work
#7
Li-Yun Zheng, Yu-Wei Lee, Yang Han, Li-Li Tang, Yu-Yan Cheng, Jin-Fa Dou, Fu-Sheng Zhou, Xiao-Dong Zheng, Hong-Yan Wang, Pei-Guang Wang, Min Gao
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomas in multiple organ systems. This study was performed in one familial and two sporadic cases with TSC. Two novel mutations (c.1884_1887delAAAG and c.5266A>G) and two previously reported mutations (c.4258_4261delTCAG and c.1960G>C) were identified by direct DNA sequencing. Of the four mutations, c.1884_1887delAAAG and c.1960G>C were found in a family and identified in the same allele by TA cloning sequencing...
May 9, 2018: Journal of Dermatology
https://www.readbyqxmd.com/read/29731980/mouse-genetic-background-influences-whether-hras-g12v-expression-plus-cdkn2a-knockdown-causes-angiosarcoma-or-undifferentiated-pleomorphic-sarcoma
#8
Laura P Brandt, Joachim Albers, Tomas Hejhal, Svende Pfundstein, Ana Filipa Gonçalves, Antonella Catalano, Peter J Wild, Ian J Frew
Soft tissue sarcomas are rare mesenchymal tumours accounting for 1% of adult malignancies and are fatal in approximately one third of patients. Two of the most aggressive and lethal forms of soft tissue sarcomas are angiosarcomas and undifferentiated pleomorphic sarcomas (UPS). To examine sarcoma-relevant molecular pathways, we employed a lentiviral gene regulatory system to attempt to generate in vivo models that reflect common molecular alterations of human angiosarcoma and UPS. Mice were intraveneously injected with MuLE lentiviruses expressing combinations of shRNA against Cdkn2a , Trp53 , Tsc2 and Pten with or without expression of HrasG12V , PIK3CAH1047R or Myc ...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29720580/targeting-mtorc1-2-complexes-inhibit-tumorigenesis-and-enhance-sensitivity-to-5-flourouracil-5-fu-in-hepatocellular-carcinoma-a-preclinical-study-of-mtorc1-2-targeted-therapy-in-hepatocellular-carcinoma-hcc
#9
Yu Zhang, Qing-An Jia, Dhruba Kadel, Xiao-Fei Zhang, Quan-Bao Zhang
BACKGROUND Although 5-Flourouracil(5-FU) is used as the first-choice treatment for advanced hepatocellular carcinoma (HCC), it is associated with acquired and intrinsic resistance. Hyperactivation of mTOR signaling has been linked to tumorigenesis and chemoresistance in HCC. The aim of this study was to evaluate and compare the antitumor effects of mTORC1 inhibitor everolimus and mTORC1/2 inhibitor AZD8055 and to examine the interaction between 5-FU and mTORC1/2 inhibitor in HCC. MATERIAL AND METHODS Using cultured HCC cells and mouse xenograft, the antitumor effects of everolimus and AZD8055 were analyzed as mono- and combination therapy with 5-Flourouracil...
May 3, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29705815/pancreatic-%C3%AE-cells-overexpressing-hiapp-impaired-mitophagy-and-unbalanced-mitochondrial-dynamics
#10
Miriam García Hernández, Ana García Aguilar, Jesús Burillo, Raquel Gómez Oca, Maria Antonietta Manca, Ana Novials, Gema Alcarraz-Vizan, Carlos Guillén, Manuel Benito
Human islet amyloid polypeptide (hIAPP), or amylin, has the tendency to aggregate into insoluble amyloid fibrils, a typical feature of islets from type 2 diabetes individuals. Thus, we investigated comparatively the impact of hIAPP on key pathways involved in pancreatic beta survival. INS1E-hIAPP cells present a hyperactivation of MTORC1 and an inhibition of autophagy signaling, those cells showing an increase in cell size. Resveratrol, a MTORC1 inhibitor, can reverse TSC2 degradation that occurs in INS1E-hIAPP cells and diminished MTORC1 hyperactivation with concomitant autophagy stimulation...
April 29, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29697822/renal-angiomyolipoma-in-patients-with-tuberous-sclerosis-complex-findings-from-the-tuberous-sclerosis-registry-to-increase-disease-awareness
#11
J Chris Kingswood, Elena Belousova, Mirjana P Benedik, Tom Carter, Vincent Cottin, Paolo Curatolo, Maria Dahlin, Lisa D' Amato, Guillaume Beaure d'Augères, Petrus J de Vries, José C Ferreira, Martha Feucht, Carla Fladrowski, Christoph Hertzberg, Sergiusz Jozwiak, John A Lawson, Alfons Macaya, Ruben Marques, Rima Nabbout, Finbar O'Callaghan, Jiong Qin, Valentin Sander, Matthias Sauter, Seema Shah, Yukitoshi Takahashi, Renaud Touraine, Sotiris Youroukos, Bernard Zonnenberg, Anna C Jansen
Background: Renal angiomyolipoma occurs at a high frequency in patients with tuberous sclerosis complex (TSC) and is associated with potentially life-threatening complications. Despite this frequency and severity, there are no large population-based cohort studies. Here we present baseline and follow-up data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with an aim to provide detailed clinical characteristics of renal angiomyolipoma among patients with TSC...
April 25, 2018: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/29688260/endocrine-disruptor-exposure-during-development-increases-incidence-of-uterine-fibroids-by-altering-dna-repair-in-myometrial-stem-cells
#12
Lauren Prusinski Fernung, Qiwei Yang, Daitoku Sakamuro, Alpana Kumari, Aymara Mas, Ayman Al-Hendy
Despite the major negative impact uterine fibroids (UFs) have on female reproductive health, little is known about early events that initiate development of these tumors. Somatic fibroid-causing mutations in MED12, the most frequent genetic alterations in UFs (up to 85% of tumors), are implicated in transforming normal myometrial stem cells (MSCs) into tumor-forming cells, though the underlying mechanism(s) leading to these mutations remains unknown. It is well-accepted that defective DNA repair increases the risk of acquiring tumor-driving mutations, though defects in DNA repair have not been explored in UF tumorigenesis...
April 24, 2018: Biology of Reproduction
https://www.readbyqxmd.com/read/29684080/unexpected-cancer-predisposition-gene-variants-in-cowden-syndrome-and-bannayan-riley-ruvalcaba-syndrome-patients-without-underlying-germline-pten-mutations
#13
Lamis Yehia, Ying Ni, Kaitlin Sesock, Farshad Niazi, Benjamin Fletcher, Hannah Jin Lian Chen, Thomas LaFramboise, Charis Eng
Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations...
April 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29683790/multicenter-phase-ib-trial-of-carboxyamidotriazole-orotate-and-temozolomide-for-recurrent-and-newly-diagnosed-glioblastoma-and-other-anaplastic-gliomas
#14
Antonio Omuro, Kathryn Beal, Katharine McNeill, Robert J Young, Alissa Thomas, Xuling Lin, Robert Terziev, Thomas J Kaley, Lisa M DeAngelis, Mariza Daras, Igor T Gavrilovic, Ingo Mellinghoff, Eli L Diamond, Andrew McKeown, Malbora Manne, Andrew Caterfino, Krishna Patel, Linda Bavisotto, Greg Gorman, Michael Lamson, Philip Gutin, Viviane Tabar, Debyani Chakravarty, Timothy A Chan, Cameron W Brennan, Elizabeth Garrett-Mayer, Rashida A Karmali, Elena Pentsova
Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle)...
April 23, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29677182/foxo-restricts-growth-and-differentiation-of-cells-with-elevated-torc1-activity-under-nutrient-restriction
#15
Katarzyna Nowak, Avantika Gupta, Hugo Stocker
TORC1, a central regulator of cell survival, growth, and metabolism, is activated in a variety of cancers. Loss of the tumor suppressors PTEN and Tsc1/2 results in hyperactivation of TORC1. Tumors caused by the loss of PTEN, but not Tsc1/2, are often malignant and have been shown to be insensitive to nutrient restriction (NR). In Drosophila, loss of PTEN or Tsc1 results in hypertrophic overgrowth of epithelial tissues under normal nutritional conditions, and an enhanced TORC1-dependent hyperplastic overgrowth of PTEN mutant tissue under NR...
April 20, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29669930/tsc2-deficient-tumors-have-evidence-of-t-cell-exhaustion-and-respond-to-anti-pd-1-anti-ctla-4-immunotherapy
#16
Heng-Jia Liu, Patrick H Lizotte, Heng Du, Maria C Speranza, Hilaire C Lam, Spencer Vaughan, Nicola Alesi, Kwok-Kin Wong, Gordon J Freeman, Arlene H Sharpe, Elizabeth P Henske
Tuberous sclerosis complex (TSC) is an incurable multisystem disease characterized by mTORC1-hyperactive tumors. TSC1/2 mutations also occur in other neoplastic disorders, including lymphangioleiomyomatosis (LAM) and bladder cancer. Whether TSC-associated tumors will respond to immunotherapy is unknown. We report here that the programmed death 1 coinhibitory receptor (PD-1) is upregulated on T cells in renal angiomyolipomas (AML) and pulmonary lymphangioleiomyomatosis (LAM). In C57BL/6J mice injected with syngeneic TSC2-deficient cells, anti-PD-1 alone decreased 105K tumor growth by 67% (P < 0...
April 19, 2018: JCI Insight
https://www.readbyqxmd.com/read/29668487/are-sporadic-eosinophilic-solid-and-cystic-renal-cell-carcinomas-characterized-by-somatic-tuberous-sclerosis-gene-mutations
#17
Megan Parilla, Sabah Kadri, Sushant A Patil, Lauren Ritterhouse, Jeremy Segal, Kammi J Henriksen, Tatjana Antic
Eosinophilic solid and cystic renal cell carcinomas (ESC RCC) is a rare, unique tumor type not yet included in the World Health Organization classification of renal neoplasia. Separately, RCCs found in patients with tuberous sclerosis complex (TSC) have recently been categorized into 3 morphologic groups: RCC with a tubulopapillary architecture separated by smooth muscle stroma, chromophobe-like, and eosinophilic-microcytic type. The third classification has been identified in ∼11% of TSC-associated RCC and have histology identical to ESC RCCs...
April 17, 2018: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29666741/a-novel-mutation-in-tsc2-gene-a-34-year-old-female-with-pulmonary-lymphangioleiomyomatosis-with-concomitant-hepatic-lesions
#18
Mehdi Nadiri, Mortaza Raeisi, Seyed Ali Mousavi Aghdas
Tuberous sclerosis complex (TSC) is an autosomal dominant disease resulting from mutation(s) in TSC1 or TSC2 genes. TSC is associated with the formation of hamartomas in the brain, heart, eyes, skin, kidneys, and lymphangioleiomyomatosis (LAM) of the lungs. LAM is almost restricted to women in reproductive age. Different mutations in TSC1 and TSC2 genes have been reported in the literature. Here, we present a female patient with TSC-LAM with a novel mutation in TSC2 gene. The patient also had multiple hepatic angiomyolipomas, which is a relatively less-reported manifestation of the disease...
2018: Case Reports in Pulmonology
https://www.readbyqxmd.com/read/29659200/atypical-tuberous-sclerosis-complex-presenting-as-familial-renal-cell-carcinoma-with-leiomyomatous-stroma
#19
Ismaël Bah, Somayyeh Fahiminiya, Louis R Bégin, Nancy Hamel, Maria Daniela D'Agostino, Simon Tanguay, William D Foulkes
We report an atypical tuberous sclerosis complex phenotype presenting as familial multiple renal cell carcinomas with (angio)leiomyomatous stroma (5/7 familial renal cell carcinomas) on a background of multiple angiomyolipomas, hypopigmented skin macules and absence of neurological anomalies. In the index case and 3 relatives, germline genetic testing identified a heterozygous TSC2 missense pathogenic variant [c.2714 G>A, (p.Arg905Gln)], a rare TSC-associated alteration which has previously been associated with a milder TSC phenotype...
April 16, 2018: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/29642873/bexarotene-inhibits-the-viability-of-non-small-cell-lung-cancer-cells-via-slc10a2-ppar%C3%AE-pten-mtor-signaling-pathway
#20
Xinghao Ai, Feng Mao, Shengping Shen, Yang Shentu, Jiejun Wang, Shun Lu
BACKGROUND: Thirty to 40 % of non-small cell lung cancer (NSCLC) patients developed higher hypertriglyceridemia in the process of treatment with bexarotene. And bioinformatics studies discovered that the expression of slc10a2 was increased in high-grade hypertriglyceridemia patients. So, we will explore the mechanism which may involve in this process. METHODS: We constructed slc10a2 overexpressed A549 cells and H1299 cells as cell models, normal A549 cells and H1299 cells as control...
April 11, 2018: BMC Cancer
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