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https://www.readbyqxmd.com/read/28423363/multiple-gene-panel-analysis-in-a-case-series-of-255-women-with-hereditary-breast-and-ovarian-cancer
#1
Gianluca Tedaldi, Michela Tebaldi, Valentina Zampiga, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Ilaria Cangini, Francesca Pirini, Elisabetta Petracci, Andrea Rocca, Fabio Falcini, Dino Amadori, Daniele Calistri
As new genes predisposing to breast (BC) and ovarian cancer (OC) are constantly emerging, the use of panels of genes analyzed by Next-Generation Sequencing (NGS) is increasing in clinical diagnostics. The identification of a large number of new germline mutations allows for deeper knowledge of cancer predisposition, although raising many questions about patient management.BC and OC patients recruited by our counseling service between 2012-2015 were included in this study. DNA was extracted from peripheral blood and a panel of 94 genes involved in hereditary tumors was analyzed by NGS...
April 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415776/targeting-protein-homeostasis-with-nelfinavir-salinomycin-dual-therapy-effectively-induces-death-of-mtorc1-hyperactive-cells
#2
Elaine A Dunlop, Charlotte E Johnson, Marie Wiltshire, Rachel J Errington, Andrew R Tee
Uncontrolled cell growth in Tuberous Sclerosis Complex occurs due to inappropriate activation of mechanistic (mammalian) target of rapamycin complex 1 (mTORC1). The current therapy, rapamycin, produced promising clinical trial results, but patient tumours regrow if treatment is discontinued, revealing rapamycin has cytostatic properties rather than a cytotoxic effect. Taking advantage of the enhanced levels of endoplasmic reticulum (ER) stress present in TSC2-null cells, we investigated drug combinations producing a cytotoxic response...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414661/delayed-presentation-of-tuberour-sclerosis-complex-in-adult-women
#3
J Manalac, S Sadd, G Akoghlanian, T Benoit-Clark
INTRODUCTION: Tuberous sclerosis complex (TSC); is an autosomal dominant disorder characterized by the formation of hamartomatous lesions in multiple organs, with a birth incidence of around one in 10,000. Although it usually manifests itself in early life, we present a case of an adult woman who we diagnosed with TSC. CASE: A 27 year old woman presented to Emergency Department with worsening right flank pain and progressive dyspnea. Physical examination findings revealed Shagreen patches and multiple angiomyolipomas of the skin...
March 2017: Journal of the Louisiana State Medical Society: Official Organ of the Louisiana State Medical Society
https://www.readbyqxmd.com/read/28414398/tuberous-sclerosis-complex-a-review
#4
Stephanie Carapetian Randle
Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can present at any age and can affect multiple organ systems. This disorder is usually identified in infants and children based on characteristic skin lesions, seizures, and cellular overgrowth or hamartomas in the heart, brain, and kidneys. Tuberous sclerosis complex is a genetic disorder caused by a mutation in either the TSC1 or TSC2 gene leading to dysfunction of hamartin or tuberin, respectively. Hamartin and tuberin form a protein complex that helps regulate cellular hyperplasia...
April 1, 2017: Pediatric Annals
https://www.readbyqxmd.com/read/28410230/insulin-growth-factor-binding-protein-2-mediates-the-progression-of-lymphangioleiomyomatosis
#5
Xiangke Li, Xiaolei Liu, Linda Zhang, Chenggang Li, Erik Zhang, Wang Ma, Qingxia Fan, Jane J Yu
Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease that almost exclusively affects women. LAM cells migrate to the lungs, where they cause cystic destruction of lung parenchyma. Mutations in TSC1 or TSC2 lead to the activation of the mammalian target of rapamycin complex-1, a kinase that regulates growth factor-dependent protein translation, cell growth, and metabolism. Insulin-like growth factor binding protein 2 (IGFBP2) binds insulin, IGF1 and IGF2 in circulation, thereby modulating cell survival, migration, and invasion in neoplasms...
March 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28409891/functional-validation-of-the-oncogenic-cooperativity-and-targeting-potential-of-tuberous-sclerosis-mutation-in-medulloblastoma-using-a-myc-amplified-model-cell-line
#6
Jacob J Henderson, Jacob P Wagner, Nicolle E Hofmann, Christopher A Eide, Yoon-Jae Cho, Brian J Druker, Monika A Davare
Medulloblastoma is the most common malignant brain tumor of childhood. To identify targetable vulnerabilities, we employed inhibitor screening that revealed mTOR inhibitor hypersensitivity in the MYC-overexpressing medulloblastoma cell line, D341. Concomitant exome sequencing unveiled an uncharacterized missense mutation, TSC2(A415V) , in these cells. We biochemically demonstrate that the TSC2(A415V) mutation is functionally deleterious, leading to shortened half-life and proteasome-mediated protein degradation...
April 14, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28409752/early-appearance-of-tuberous-sclerosis-complex-on-cerebral-ultrasound-in-extremely-preterm-infant
#7
E B F Terpstra-Prinsen, K Kamphuis-Van Ulzen, K D Liem
Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder. Diagnosis of early onset TSC in newborn infants is usually made by cardiac ultrasound because of circulatory problems due to cardiac rhabdomyoma. Early appearance of cortical tubers on cerebral ultrasound in newborn infants is very rare. Mostly TSC is diagnosed on MRI and not by cerebral ultrasound. Subependymal nodules are the usual presenting sign of TSC on cerebral ultrasound in neonates, which are often misdiagnosed as subependymal hemorrhage, calcifications or ischemic lesions after intrauterine germinal matrix hemorrhage...
April 8, 2017: Journal of Neonatal-perinatal Medicine
https://www.readbyqxmd.com/read/28397210/-analysis-of-tsc-gene-mutations-in-five-patients-with-tuberous-sclerosis-complex
#8
Linli Liu, Zhengzhong Zhang, Yunzhu Mu, Fen Xiong, Hao Yang, Ping Yang, Yiping Liu, Xing Chen, Weichi Sui
OBJECTIVE: To identify pathogenic mutations of TSC1 and TSC2 genes in two familial and one sporadic cases with tuberous sclerosis complex (TSC). METHODS: For five patients and their family members, potential mutations of the TSC1 and TSC2 genes were detected by direct sequencing. RESULTS: For one family, a novel missense mutation c.1964C>T (p.S655F) was detected in the exon 19 of the TSC2 gene. For the sporadic patient, a repeat substitution with deletion mutation c...
April 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28387735/tcs2-increases-olaquindox-induced-apoptosis-by-upregulation-of-ros-production-and-downregulation-of-autophagy-in-hek293-cells
#9
Daowen Li, Kena Zhao, Xiayun Yang, Xilong Xiao, Shusheng Tang
Olaquindox, a feed additive, has drawn public attention due to its potential mutagenicity, genotoxicity, hepatoxicity and nephrotoxicity. The purpose of this study was to investigate the role of tuberous sclerosis complex (TSC2) pathways in olaquindox-induced autophagy in human embryonic kidney 293 (HEK293) cells. The results revealed that olaquindox treatment reduced the cell viability of HEK293 cells and downregulated the expression of TSC2 in a dose- and time-dependent manner. Meanwhile, olaquindox treatment markedly induced the production of reactive oxygen species (ROS), cascaded to autophagy, oxidative stress, and apoptotic cell death, which was effectively eliminated by the antioxidant N-acetylcysteine (NAC)...
April 7, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28386314/recent-advances-and-challenges-of-mtor-inhibitors-use-in-the-treatment-of-patients-with-tuberous-sclerosis-complex
#10
REVIEW
Filipe Palavra, Conceição Robalo, Flávio Reis
Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28382513/rna-splicing-and-splicing-regulator-changes-in-prostate-cancer-pathology
#11
REVIEW
Jennifer Munkley, Karen Livermore, Prabhakar Rajan, David J Elliott
Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA...
April 5, 2017: Human Genetics
https://www.readbyqxmd.com/read/28367235/combined-targeting-of-mtor-and-akt-using-rapamycin-and-mk-2206-in-the-treatment-of-tuberous-sclerosis-complex
#12
Shuang Ji, Wei Lin, Li Wang, Zhaofei Ni, Fuquan Jin, Xiaojun Zha, Guanghe Fei
Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in the TSC1 or TSC2 genes, is an autosomal dominant disease characterized by benign tumor formation in multiple organs. Hyperactivation of mammalian target of rapamycin (mTOR) is the primary alteration underlying TSC tumor. Thus, rapamycin, as an mTOR specific inhibitor, has been assumed as a potential drug for the treatment of TSC. However, its application in TSC patients has been limited due to side effects. By analyzing Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs), we found that loss of TSC1 or TSC2 led to a decreased sensitivity to MK-2206, a novel allosteric Akt inhibitor...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28361047/dynamic-akt-mtor-signaling-in-children-with-autism-spectrum-disorder
#13
Charity Onore, Houa Yang, Judy Van de Water, Paul Ashwood
Autism spectrum disorder (ASD) is a behaviorally defined disorder affecting 1 in 68 children. Currently, there is no known cause for the majority of ASD cases nor are there physiological diagnostic tools or biomarkers to aid behavioral diagnosis. Whole-genome linkage studies, genome-wide association studies, copy number variation screening, and SNP analyses have identified several ASD candidate genes, but which vary greatly among individuals and family clusters, suggesting that a variety of genetic mutations may result in a common pathology or alter a common mechanistic pathway...
2017: Frontiers in Pediatrics
https://www.readbyqxmd.com/read/28349193/time-matched-analysis-of-dna-adduct-formation-and-early-gene-expression-as-predictive-tool-for-renal-carcinogenesis-in-methylazoxymethanol-acetate-treated-eker-rats
#14
Valentina Klaus, Heinke Bastek, Katja Damme, Leonard B Collins, Roland Frötschl, Norbert Benda, Dominik Lutter, Heidrun Ellinger-Ziegelbauer, James A Swenberg, Daniel R Dietrich, Kerstin Stemmer
Genotoxic carcinogens pose great hazard to human health. Uncertainty of current risk assessment strategies and long latency periods between first carcinogen exposure and diagnosis of tumors have raised interest in predictive biomarkers. Initial DNA adduct formation is a necessary step for genotoxin induced carcinogenesis. However, as DNA adducts not always translate into tumorigenesis, their predictive value is limited. Here we hypothesize that the combined analysis of pro-mutagenic DNA adducts along with time-matched gene expression changes could serve as a superior prediction tool for genotoxic carcinogenesis...
March 27, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28347844/complex-inhibition-of-autophagy-by-mitochondrial-aldehyde-dehydrogenase-shortens-lifespan-and-exacerbates-cardiac-aging
#15
Yingmei Zhang, Cong Wang, Jingmin Zou, Aijun Sun, Lindsay K Hueckstaedt, Junbo Ge, Jun Ren
Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a cascade of biological processes including aging. A number of autophagy regulators have been identified. Here we demonstrated that mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme with the most common single point mutation in humans, governs cardiac aging through regulation of autophagy. Myocardial mechanical and autophagy properties were examined in young (4 mo) and old (26-28 mo) wild-type (WT) and global ALDH2 transgenic mice...
March 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28344003/abnormal-neural-progenitor-cells-differentiated-from-induced-pluripotent-stem-cells-partially-mimicked-development-of-tsc2-neurological-abnormalities
#16
Yaqin Li, Jiqing Cao, Menglong Chen, Jing Li, Yiming Sun, Yu Zhang, Yuling Zhu, Liang Wang, Cheng Zhang
Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells...
April 11, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28336152/development-of-hypomelanotic-macules-is-associated-with-constitutive-activated-mtorc1-in-tuberous-sclerosis-complex
#17
Lisbeth Birk Møller, Bitten Schönewolf-Greulich, Thomas Rosengren, Lasse Jonsgaard Larsen, John R Ostergaard, Mette Sommerlund, Caroline Ostenfeldt, Brian Stausbøl-Grøn, Karen Markussen Linnet, Pernille Axél Gregersen, Uffe Birk Jensen
TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1838Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype...
March 1, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28327903/successful-mtor-inhibitor-therapy-for-a-metastastic-neuroendocrine-tumour-in-a-patient-with-a-germline-tsc2-mutation
#18
J Schrader, F O Henes, D Perez, S Burdak-Rothkamm, A Stein, J R Izbicki, A W Lohse
No abstract text is available yet for this article.
April 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28322282/maternal-immune-activation-dysregulation-of-the-fetal-brain-transcriptome-and-relevance-to-the-pathophysiology-of-autism-spectrum-disorder
#19
M V Lombardo, H M Moon, J Su, T D Palmer, E Courchesne, T Pramparo
Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations...
March 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28302666/mtorc1-signalling-mediates-pi3k-dependent-large-lipid-droplet-accumulation-in-drosophila-ovarian-nurse-cells
#20
Lawrence B Mensah, Deborah C I Goberdhan, Clive Wilson
Insulin and insulin-like growth factor signalling (IIS), which is primarily mediated by the PI3-kinase (PI3K)/PTEN/Akt kinase signalling cassette, is a highly evolutionary conserved pathway involved in co-ordinating growth, development, ageing and nutrient homeostasis with dietary intake. It controls transcriptional regulators, in addition to promoting signalling by mechanistic Target of Rapamycin (mTOR) Complex 1 (mTORC1), which stimulates biosynthesis of proteins and other macromolecules, and drives organismal growth...
March 16, 2017: Biology Open
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