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Siying Ren, Yongfeng Luo, Hui Chen, David Warburton, Hilaire C Lam, Larry Wang, Ping Chen, Elizabeth P Henske, Wei Shi
The tuberous sclerosis complex (TSC) proteins are critical negative regulators of the mTORC1 pathway. Germline mutations of TSC1 or TSC2 cause TSC, affecting multiple organs, including the kidney and lung, and causing substantial morbidity and mortality. The mechanisms of organ-specific disease in TSC remain incompletely understood, and the impact of TSC inactivation on mesenchymal lineage cells has not been specifically studied. We deleted Tsc2 specifically in mesoderm-derived mesenchymal cells of multiple organs in mice using the Dermo1-Cre driver...
October 18, 2016: American Journal of Pathology
Walid Briki
Motivation toward physical exercise (MPE) and trait self-control (TSC) were identified as key predictors of subjective wellbeing (SWB). However, there has not been any research designed to examine the mediating role of TSC in the relationship between MPE and SWB. The present study utilizes self-determination theory, control-process theory of self-regulation, and theory of multiple pathways of TSC in order to examine whether TSC mediates the relationships of autonomous MPE (A-MPE), controlled MPE (C-MPE), and impersonal MPE (NO-MPE) with SWB using structural equation modeling (XLSTAT PLS)...
2016: Frontiers in Psychology
Darius Ebrahimi-Fakhari, Afshin Saffari, Lara Wahlster, Alessia Di Nardo, Daria Turner, Tommy L Lewis, Christopher Conrad, Jonathan M Rothberg, Jonathan O Lipton, Stefan Kölker, Georg F Hoffmann, Min-Joon Han, Franck Polleux, Mustafa Sahin
Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown. Here, we demonstrate impaired mitochondrial homeostasis in neuronal in vitro and in vivo models of TSC...
October 18, 2016: Cell Reports
Piotr T Filipczak, Cynthia L Thomas, Wenshu Chen, Andrew Salzman, Jacob D McDonald, Yong Lin, Steven A Belinsky
Tuberous sclerosis complex (TSC) is a genetic multi-organ disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach...
October 18, 2016: Cancer Research
Barbara Kathage, Sebastian Gehlert, Anna Ulbricht, Laura Lüdecke, Victor E Tapia, Zacharias Orfanos, Daniela Wenzel, Wilhelm Bloch, Rudolf Volkmer, Bernd K Fleischmann, Dieter O Fürst, Jörg Höhfeld
The cochaperone BAG3 is a central protein homeostasis factor in mechanically strained mammalian cells. It mediates the degradation of unfolded and damaged forms of the actin-crosslinker filamin through chaperone-assisted selective autophagy (CASA). In addition, BAG3 stimulates filamin transcription in order to compensate autophagic disposal and to maintain the actin cytoskeleton under strain. Here we demonstrate that BAG3 coordinates protein synthesis and autophagy through spatial regulation of the mammalian target of rapamycin complex 1 (mTORC1)...
October 15, 2016: Biochimica et Biophysica Acta
Hilaire C Lam, Julie S Nijmeh, Elizabeth P Henske
In just the past five years, dramatic changes have occurred in the clinical management of Tuberous Sclerosis Complex (TSC). Detailed knowledge about the role of the TSC proteins in regulating the activity of the mammalian Target of Rapamycin Complex 1 (mTORC1) underlies this paradigm-shifting progress. Advances continue to be made in understanding the genetic pathogenesis of the different tumours that occur in TSC, including pivotal discoveries using next-generation sequencing (NGS). For example, the pathogenesis of angiofibromas is now known to involve UV-induced mutations, and the pathogenesis of multifocal renal cell carcinoma (RCC) in TSC is now known to result from distinct second-hit mutations...
October 18, 2016: Journal of Pathology
Theresa Scholl, Angelika Mühlebner, Gerda Ricken, Victoria Gruber, Anna Fabing, Sharon Samueli, Gudrun Gröppel, Christian Dorfer, Thomas Czech, Johannes A Hainfellner, Avanita S Prabowo, Roy J Reinten, Lisette Hoogendijk, Jasper J Anink, Eleonora Aronica, Martha Feucht
Conventional antiepileptic drugs suppress the excessive firing of neurons during seizures. In drug-resistant patients, treatment failure indicates an alternative important epileptogenic trigger. Two epilepsy-associated pathologies show myelin deficiencies in seizure-related brain regions: Focal Cortical Dysplasia IIB (FCD) and cortical tubers in Tuberous Sclerosis Complex (TSC). Studies uncovering white matter-pathology mechanisms are therefore urgently needed to gain more insight into epileptogenesis, the propensity to maintain seizures, and their associated comorbidities such as cognitive defects...
October 17, 2016: Brain Pathology
Samara L Potter, Rajkumar Venkatramani, Scott Wenderfer, Brett H Graham, Sanjeev A Vasudevan, Andrew Sher, Hao Wu, David A Wheeler, Yaping Yang, Christine M Eng, Richard A Gibbs, Angshumoy Roy, Sharon E Plon, D Williams Parsons
Pediatric renal cell carcinoma (RCC) is a rare cancer that can be associated with inherited diseases including tuberous sclerosis complex (TSC) caused by germline mutations in TSC1 or TSC2. Somatic mutations in TSC1 and TSC2 have also been reported in adult RCC, which predict response to mTOR inhibitors. Here, we present the first case of RCC in a child with methylmalonic acidemia (MMA). Clinical whole exome sequencing of blood and tumor samples confirmed the diagnosis of MMA and revealed two somatic inactivating mutations in TSC2, suggesting the potential consideration of an mTOR inhibitor in the event of tumor recurrence...
October 17, 2016: Pediatric Blood & Cancer
Jasna Jančić, Vesna Đurić, Nikola Ivančević, Blažo Nikolić, John N van den Anker, Janko Samardžić
The serine/threonine kinase mechanistic target of rapamycin (mTOR) is an important sensor of the cellular energy condition which, at the same time, represents a kind of master switch between anabolic and catabolic cellular processes. Tuberous sclerosis complex (TSC) is a genetic disease which is considered to be a prototype of a dysregulated mTOR signaling pathway. The dysregulated mTOR pathway in TSC leads to characteristic structural and physiologic abnormalities in multiple organs. In this review we focus on the pharmacological properties of mTOR inhibitors and clinical investigations of mTOR inhibitors for two important neurological TSC manifestations: subependymal giant cell astrocytomas (SEGAs) and epilepsy...
October 12, 2016: Current Medicinal Chemistry
Raouf Seyam, Waleed Al Khudair, Said A Kattan, Mohammed Faihan Al, Fawaz Skaff, Waleed Mohamad AlTaweel
BACKGROUND: There is a growing concern that renal impairment may develop in patients with renal angiomyolipomas (AMLs) associated with tuberous sclerosis complex (TSC) as a consequence of the disease itself and/or the interventions to mitigate the risk of hemorrhage. OBJECTIVE: To assess the estimated glomerular filtration rate (eGFR) in patients with bilateral renal AMLs and the impact of tumor burden and intervention on renal function. DESIGN: Retrospective study...
September 2016: Annals of Saudi Medicine
Fatemeh Javadi, Arman Ahmadzadeh, Shahryar Eghtesadi, Naheed Aryaeian, Mozhdeh Zabihiyeganeh, Abbas Rahimi Foroushani, Shima Jazayeri
OBJECTIVE: Previous studies have shown that the bioflavonoid quercetin has anti-inflammatory and anti-nociceptive effects. We investigated the effect of quercetin supplementation on inflammation, disease severity, and clinical symptoms in women with rheumatoid arthritis (RA). METHODS: The present study was a randomized, double-blind, placebo-controlled clinical trial in which 50 women with RA were allocated into a quercetin (500 mg/day) or placebo group for 8 weeks...
October 6, 2016: Journal of the American College of Nutrition
Kallayi Nabeela, Reny Thankam Thomas, Jyothi B Nair, Kaustabh Kumar Maiti, Krishna Gopa Kumar Warrier, Saju Pillai
Synthesis of shape-tuned silver (Ag) nanostructures with high plasmon characteristics has drawn significant importance in in-vitro diagnostic applications. Herein, we report a simple aqueous synthetic route using TEMPO-oxidized nanocellulose fibers (T-NCF) and trisodium citrate (TSC) that results in anisotropically grown flower-like Ag nanoconstruct (AgNF). A detailed investigation of the concentration and sequence of the addition of reactants on the formation of these anisotropic Ag structure is presented...
October 6, 2016: ACS Applied Materials & Interfaces
Samy L Habib, Noor Y Al-Obaidi, Maciej Nowacki, Katarzyna Pietkun, Barbara Zegarska, Tomasz Kloskowski, Wojciech Zegarski, Tomasz Drewa, Edward A Medina, Zhenze Zhao, Sitai Liang
Tuberous sclerosis complex (TSC) is an autosomal dominant and multi-system genetic disorder in humans. TSC affects around 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders. TSC is caused by defects or mutations in two genes, TSC1 and TSC2. Loss of TSC1/TSC2 leads to dysregulation of mTOR, resulting in aberrant cell differentiation and development, and abnormal enlargement of cells...
2016: Journal of Cancer
Evan J Hess, Kirsten A Moody, Alexandra L Geffrey, Sarah F Pollack, Lauren A Skirvin, Patricia L Bruno, Jan L Paolini, Elizabeth A Thiele
OBJECTIVE: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC...
October 2016: Epilepsia
Tohru Okanishi, Tomoyuki Akiyama, Ellen Mayo, Yasunori Honda, Chihiro Ueda-Kawada, Midori Nakajima, Yoichiro Homma, Ayako Ochi, Cristina Go, Elysa Widjaja, Sylvester H Chuang, James T Rutka, James Drake, O Carter Snead, Hiroshi Otsubo
OBJECTIVE: We hypothesized that the extensive epileptic network in patients with tuberous sclerosis complex (TSC) manifests as clustered and scattered distributions of magnetoencephalography spike sources (MEGSS). METHODS: We retrospectively analyzed pre-surgical MEG in 15 patients with TSC. We performed single moving dipole analysis to localize and classify clustered and scattered MEGSS. We compared the number of electrodes within the resected area (RA) and the proportions of clustered and scattered MEGSS within RA with the seizure outcome...
September 6, 2016: Epilepsy Research
Sanjay Konakondla, Mayur Jayarao, Jami Skrade, Caterina Giannini, Michael J Workman, Chad J Morgan
INTRODUCTION: The well-described entity of Subependymal Giant Cell Astrocytoma (SEGA) in the setting of Tuberous Sclerosis Complex (TSC) is profound in current literature. It has been described in children as well as adults with or without identifiable clinical presentations of tuberous sclerosis. To our knowledge there has not been any report of a negative genetic workup of Tuberous Sclerosis Complex in an adult patient presenting with an isolated SEGA. CASE REPORT: We present a case of a 25-year-old female with no medical history who presented to the emergency room for headaches...
November 2016: Clinical Neurology and Neurosurgery
S Brakemeier, C Grohé, F Bachmann, K Budde
No abstract text is available yet for this article.
September 29, 2016: Pneumologie
Suraj Peri, Elena Caretti, Rossella Tricarico, Karthik Devarajan, Mitchell Cheung, Eleonora Sementino, Craig W Menges, Emmanuelle Nicolas, Lisa A Vanderveer, Sharon Howard, Peggy Conrad, James A Crowell, Kerry S Campbell, Eric A Ross, Andrew K Godwin, Anthony T Yeung, Margie L Clapper, Robert G Uzzo, Elizabeth P Henske, Christopher J Ricketts, Cathy D Vocke, W Marston Linehan, Joseph R Testa, Alfonso Bellacosa, Levy Kopelovich, Alfred G Knudson
Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal "one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC)...
September 22, 2016: Oncotarget
Tim Cardilin, Joachim Almquist, Mats Jirstrand, Alexandre Sostelly, Christiane Amendt, Samer El Bawab, Johan Gabrielsson
Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h(-1) and the natural cell death to 0.0039 h(-1) resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound...
September 28, 2016: AAPS Journal
Joanna Trelinska, Wojciech Fendler, Iwona Dachowska, Katarzyna Kotulska, Sergiusz Jozwiak, Karolina Antosik, Piotr Gnys, Maciej Borowiec, Wojciech Mlynarski
BACKGROUND: Tuberous sclerosis (TSC) is a monogenic disease resulting from defects of the TSC1 or TSC2 genes, which encode the proteins forming hamartin-tuberin tumor suppressor complex, the mammalian target of rapamycin complex (mTOR). The mTOR pathway is constitutively activated in response to tuberin or hamartin defects. The mTOR pathway is also regulated by a multitude of epigenetic mechanisms, one of which is regulation by microRNA (miRNA) inhibition. This leads us to hypothesize that organ-level abnormalities of miRNA expression patterns are widespread in TSC...
September 29, 2016: Orphanet Journal of Rare Diseases
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