scholarly journals The Tuberous Sclerosis Complex–Mammalian Target of Rapamycin Pathway Maintains the Quiescence and Survival of Naive T Cells

2011 ◽  
Vol 187 (3) ◽  
pp. 1106-1112 ◽  
Author(s):  
Qi Wu ◽  
Yu Liu ◽  
Chong Chen ◽  
Tsuneo Ikenoue ◽  
Yu Qiao ◽  
...  
Keyword(s):  
T Cells ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Naive T Cells ◽  
Naïve T Cells

scholarly journals Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma

2008 ◽  
Vol 14 (9) ◽  
pp. 2543-2550 ◽  
Author(s):  
Karen H. Lu ◽  
Weiguo Wu ◽  
Bhuvanesh Dave ◽  
Brian M. Slomovitz ◽  
Thomas W. Burke ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin

Rapid regression of large cardiac rhabdomyomas in neonates after sirolimus therapy

2017 ◽  
Vol 28 (3) ◽  
pp. 485-489 ◽  
Author(s):  
M. David Weiland ◽  
Kristin Bonello ◽  
Kevin D. Hill
Keyword(s):  
Clinical Trials ◽  
Tuberous Sclerosis ◽  
Surgical Resection ◽  
Tuberous Sclerosis Complex ◽  
Spontaneous Regression ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Rapid Regression

AbstractCardiac rhabdomyomas are the most common tumours in children and are typically seen in association with the tuberous sclerosis complex. Although benign and often associated with spontaneous regression, in rare circumstances surgical resection is indicated to relieve obstruction or other mass-related effects. Recent clinical trials have demonstrated the benefits of mammalian target of rapamycin inhibitors for the treatment of other tumour sub-types associated with tuberous sclerosis. Here we report rapid regression of several massive cardiac rhadomyomas in two neonates with the use of the mammalian target of rapamycin inhibitor sirolimus.

Congenital Segmental Lymphedema in Tuberous Sclerosis Complex With Associated Subependymal Giant Cell Astrocytomas Treated with Mammalian Target of Rapamycin Inhibitors

2013 ◽  
Vol 29 (9) ◽  
pp. NP54-NP57 ◽  
Author(s):  
Giulia Prato ◽  
Maria Margherita Mancardi ◽  
Maria Giuseppina Baglietto ◽  
Sara Janis ◽  
Nadia Vercellino ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Giant Cell ◽  
Tuberous Sclerosis Complex ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin

scholarly journals “TOR” rents of Excitement over Rapamycin's Antiepileptogenic Potential

2008 ◽  
Vol 8 (6) ◽  
pp. 163-165
Author(s):  
Lisa R. Merlin
Keyword(s):  
Tuberous Sclerosis ◽  
Median Survival ◽  
Tuberous Sclerosis Complex ◽  
Early Treatment ◽  
Mammalian Target Of Rapamycin ◽  
Premature Death ◽  
Neuronal Model ◽  
Akt Signaling ◽  
Target Of Rapamycin ◽  
Late Treatment

Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function. Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, Kwiatkowski DJ. J Neurosci 2008;28(21):5422–5432. Tuberous sclerosis (TSC) is a hamartoma syndrome attributable to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have reported recently (Meikle et al., 2007) a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001 [40- O-(2-hydroxyethyl)-rapamycin], both mammalian target of rapamycin mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 d to more than 100 d; behavior, phenotype, and weight gain are all also markedly improved. There is brain penetration of both drugs, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream target of mTORC1. In addition, there is restoration of phospho-Akt and phospho-glycogen synthase kinase 3 levels in the treated mice, consistent with restoration of Akt function. Neurofilament abnormalities, myelination, and cell enlargement are all improved by the treatment. However, dysplastic neuronal features persist, and there are only modest changes in dendritic spine density and length. Strikingly, mice treated with rapamycin or RAD001 for 23 d only (postnatal days 7–30) displayed a persistent improvement in phenotype, with median survival of 78 d. In summary, rapamycin/RAD001 are highly effective therapies for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signaling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms. Rapamycin Prevents Epilepsy in a Mouse Model of Tuberous Sclerosis Complex. Zeng LH, Xu L, Gutmann DH, Wong M. Ann Neurol 2008;63(4):444–453. OBJECTIVE: Tuberous sclerosis complex (TSC) represents one of the most common genetic causes of epilepsy. TSC gene inactivation leads to hyperactivation of the mammalian target of rapamycin signaling pathway, raising the intriguing possibility that mammalian target of rapamycin inhibitors might be effective in preventing or treating epilepsy in patients with TSC. Mice with conditional inactivation of the Tsc1 gene primarily in glia ( Tsc1GFAPCKO mice) develop glial proliferation, progressive epilepsy, and premature death. Here, we tested whether rapamycin could prevent or reverse epilepsy, as well as other cellular and molecular brain abnormalities in Tsc1GFAPCKO mice. METHODS: Tsc1GFAPCKO mice and littermate control animals were treated with rapamycin or vehicle starting at postnatal day 14 (early treatment) or 6 weeks of age (late treatment), corresponding to times before and after onset of neurological abnormalities in Tsc1GFAPCKO mice. Mice were monitored for seizures by serial video-electroencephalogram and for long-term survival. Brains were examined histologically for astrogliosis and neuronal organization. Expression of phospho-S6 and other molecular markers correlating with epileptogenesis was measured by Western blotting. RESULTS: Early treatment with rapamycin prevented the development of epilepsy and premature death observed in vehicle-treated Tsc1GFAPCKO mice. Late treatment with rapamycin suppressed seizures and prolonged survival in Tsc1GFAPCKO mice that had already developed epilepsy. Correspondingly, rapamycin inhibited the abnormal activation of the mammalian target of rapamycin pathway, astrogliosis, and neuronal disorganization, and increased brain size in Tsc1GFAPCKO mice. INTERPRETATION: Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1GFAPCKO mice.

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