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rapamycin aging

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https://www.readbyqxmd.com/read/28416958/keratinization-of-lung-squamous-cell-carcinoma-is-associated-with-poor-clinical-outcome
#1
Hye Jung Park, Yoon-Jin Cha, Seong Han Kim, Arum Kim, Eun Young Kim, Yoon Soo Chang
BACKGROUND: Although the World Health Organization (WHO) classification of lung squamous cell carcinoma (SCC) was revised in 2015, its clinical implications for lung SCC subsets remain unclear. We investigated whether the morphologic characteristics of lung SCC, including keratinization, were associated with clinical parameters and clinical outcome of patients. METHODS: A total of 81 patients who underwent curative surgical resection of diagnosed lung SCC, were enrolled in this study...
April 2017: Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/28413127/evolution-of-circulating-tumor-dna-profile-from-first-line-to-subsequent-therapy-in-metastatic-renal-cell-carcinoma
#2
Sumanta K Pal, Guru Sonpavde, Neeraj Agarwal, Nicholas J Vogelzang, Sandy Srinivas, Naomi B Haas, Sabina Signoretti, Bradley A McGregor, Jeremy Jones, Richard B Lanman, Kimberly C Banks, Toni K Choueiri
BACKGROUND: Treatment of metastatic renal cell carcinoma (mRCC) typically entails mechanistically distinct agents across the first- and second-line setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. Circulating tumor DNA (ctDNA) is a platform to noninvasively ascertain temporal changes in genomic profile. OBJECTIVE: To assess the ctDNA profile in a large cohort of mRCC patients, and to assess changes across patients receiving first-line and later lines of therapy...
April 13, 2017: European Urology
https://www.readbyqxmd.com/read/28410911/comprehensive-analysis-of-survival-outcomes-in-non-clear-cell-renal-cell-carcinoma-patients-treated-in-clinical-trials
#3
Guillermo de Velasco, Rana R McKay, Xun Lin, Raphel B Moreira, Ronit Simantov, Toni K Choueiri
BACKGROUND: Clinical data from patients with non-clear cell renal cell carcinoma (nccRCC) receiving targeted therapy are limited, and many clinical trials have excluded these patients from study entry. We sought to investigate the outcomes of patients with nccRCC treated in clinical trials in the modern era compared with the outcomes of patients with clear cell RCC (ccRCC). PATIENTS AND METHODS: We conducted a retrospective study of patients with metastatic RCC who had received targeted therapy in Pfizer-sponsored phase II and III clinical trials from 2003 to 2013...
March 21, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28410084/clinical-and-electroencephalographic-characteristics-of-infantile-onset-epilepsies-caused-by-genetic-mutations
#4
Yun Jung Hur, Sookyong Koh, John Millichap, Srishti Nangia, Lawrence J Jennings, Douglas R Nordli
OBJECTIVES: To determine whether certain characteristic electroencephalography (EEG) features are indicative of a genetic cause in early-life epilepsy. STUDY DESIGN: We enrolled a total of 100 patients with infantile-onset (<3 years) epilepsy due to known genetic cause (n?=?50) and nongenetic cause (acquired, structural, or unknown, n?=?50). The genetic group was classified into synaptopathies, channelopathies, mTOR (mammalian target of rapamycin)-opathies, and chromosomal abnormalities...
March 2, 2017: Journal of Pediatrics
https://www.readbyqxmd.com/read/28400571/moderate-lifelong-overexpression-of-tuberous-sclerosis-complex-1-tsc1-improves-health-and-survival-in-mice
#5
Hong-Mei Zhang, Vivian Diaz, Michael E Walsh, Yiqiang Zhang
The tuberous sclerosis complex 1/2 (TSC1/2) is an endogenous regulator of the mechanistic target of rapamycin (mTOR). While mTOR has been shown to play an important role in health and aging, the role of TSC1/2 in aging has not been fully investigated. In the current study, a constitutive TSC1 transgenic (Tsc1 (tg) ) mouse model was generated and characterized. mTORC1 signaling was reduced in majority of the tissues, except the brain. In contrast, mTORC2 signaling was enhanced in Tsc1 (tg) mice. Tsc1 (tg) mice are more tolerant to exhaustive exercises and less susceptible to isoproterenol-induced cardiac hypertrophy at both young and advanced ages...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28394250/ampk-and-vacuole-associated-atg14p-orchestrate-%C3%A2%C2%B5-lipophagy-for-energy-production-and-long-term-survival-under-glucose-starvation
#6
Arnold Young Seo, Pick-Wei Lau, Daniel Feliciano, Prabuddha Sengupta, Mark A Le Gros, Bertrand Cinquin, Carolyn A Larabell, Jennifer Lippincott-Schwartz
Dietary restriction increases the longevity of many organisms but the cell signaling and organellar mechanisms underlying this capability are unclear. We demonstrate that to permit long-term survival in response to sudden glucose depletion, yeast cells activate lipid-droplet (LD) consumption through micro-lipophagy (µ-lipophagy), in which fat is metabolized as an alternative energy source. AMP-activated protein kinase (AMPK) activation triggered this pathway, which required Atg14p. More gradual glucose starvation, amino acid deprivation or rapamycin did not trigger µ-lipophagy and failed to provide the needed substitute energy source for long-term survival...
April 10, 2017: ELife
https://www.readbyqxmd.com/read/28393891/progressive-slowdown-prevention-of-cellular-senescence-by-cd9-targeted-delivery-of-rapamycin-using-lactose-wrapped-calcium-carbonate-nanoparticles
#7
Raj Kumar Thapa, Hanh Thuy Nguyen, Jee-Heon Jeong, Jae Ryong Kim, Han-Gon Choi, Chul Soon Yong, Jong Oh Kim
Cellular senescence, a state of irreversible growth arrest and altered cell function, causes aging-related diseases. Hence, treatment modalities that could target aging cells would provide a robust therapeutic avenue. Herein, for the first time, we utilized CD9 receptors (overexpressed in senescent cells) for nanoparticle targeting in addition to the inherent β-galactosidase activity. In our study, CD9 monoclonal antibody-conjugated lactose-wrapped calcium carbonate nanoparticles loaded with rapamycin (CD9-Lac/CaCO3/Rapa) were prepared for targeted rapamycin delivery to senescent cells...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28390264/selected-life-extending-interventions-reduce-arterial-cxcl10-and-macrophage-colony-stimulating-factor-in-aged-mouse-arteries
#8
Daniel W Trott, Lisa A Lesniewski, Anthony J Donato
Cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Aging is the most predictive risk factor for CVD and is associated with arterial inflammation which contributes to increased CVD risk. Although age-related arterial inflammation has been described in both humans and animals, only a limited number of inflammatory mediators, cytokines and chemokines have been identified. In this investigation we sought to determine whether lifespan extending interventions, including crowded litter early life nutrient deprivation (CL), traditional lifelong caloric restriction (CR) and lifelong Rapamycin treatment (Rap) would attenuate age-related arterial inflammation using multi analyte profiling...
April 5, 2017: Cytokine
https://www.readbyqxmd.com/read/28385537/phase-i-trial-of-everolimus-and-capecitabine-in-metastatic-her2-breast-cancer
#9
Gregory A Vidal, Mary Chen, Shruti Sheth, Tiffany Svahn, Ellie Guardino
BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is a driver of breast tumorigenesis. The mTOR inhibitor everolimus reverses antihormonal therapy resistance and is an approved therapy for metastatic breast cancer. A synergistic effect with fluoropyrimidine has been suggested. The present study evaluated the safety and tolerability of an all-oral combination of everolimus and capecitabine for metastatic breast cancer (MBC). PATIENTS AND METHODS: MBC patients naive to capecitabine and mTOR inhibitors who had received ≤ 3 previous chemotherapy regimens in the metastatic setting were eligible for the present study...
March 16, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/28380520/the-addition-of-protein-bound-amino-acids-in-low-protein-diets-improves-the-metabolic-and-immunological-characteristics-in-fifteen-to-thirty-five-kg-pigs
#10
L Q Che, X Peng, L Hu, C Wu, Q Xu, Z F Fang, Y Lin, S Y Xu, J Li, B Feng, G Tian, R N Zhang, H Sun, D Wu, D W Chen
This study was to evaluate the effects of supplementation of AA form (crystalline vs. protein bound) in low-protein diets on growth, metabolic, and immunological characteristics of pigs. A total of 80 barrows (PIC 327 × 1050; 15.57 ± 0.13 kg BW and 48 ± 2 d of age), housed in 4 pigs per pen with 5 pens per treatment, were assigned to 4 dietary treatments of 17, 15, and 13% CP and 13% CP plus casein for 28 d. The crystalline AA were supplemented to meet the requirement of indispensable AA in pigs. Results showed that pigs fed the 13% CP diet or the 13% CP plus casein diet had lower ( < 0...
March 2017: Journal of Animal Science
https://www.readbyqxmd.com/read/28379293/cell-autonomous-requirement-for-mammalian-target-of-rapamycin-mtor-in-spermatogonial-proliferation-and-differentiation-in-the-mouse4
#11
Nicholas D Serra, Ellen K Velte, Bryan A Niedenberger, Oleksander Kirsanov, Christopher B Geyer
Spermatogonial stem cells (SSCs) must balance self-renewal with production of transit-amplifying progenitors that differentiate in response to retinoic acid (RA) before entering meiosis. This self-renewal vs. differentiation fate decision is critical for maintaining tissue homeostasis, as imbalances cause defects that can lead to human testicular cancer or infertility. Little is currently known about the program of differentiation initiated by RA, and the pathways and proteins involved are poorly defined. We recently found that RA stimulation of the PI3K/AKT/mTOR kinase signaling pathway is required for differentiation, and that short-term inhibition of mTOR complex 1 (mTORC1) by rapamycin blocked spermatogonial differentiation in vivo and prevented RA-induced translational activation...
March 31, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28374506/g-csf-and-cognitive-dysfunction-in-elderly-diabetic-mice-with-cerebral-small-vessel-disease-preventive-intervention-effects-and-underlying-mechanisms
#12
Zhu-Fei Guan, Ying-Hong Tao, Xiao-Ming Zhang, Qi-Lin Guo, Ying-Chao Liu, Yu Zhang, Yan-Mei Wang, Gang Ji, Guo-Feng Wu, Na-Na Wang, Hao Yang, Zhong-Yu Yu, Jing-Chun Guo, Hou-Guang Zhou
AIMS: Although cognitive dysfunction is a common neurological complication in elderly patients with diabetes, the mechanisms underlying this relationship remain unclear, and effective preventive interventions have yet to be developed. Thus, this study investigated the preventive effects and mechanisms of action associated with granulocyte colony-stimulating factor (G-CSF) on cognitive dysfunction in elderly diabetic mice with cerebral small vessel disease. METHODS: This study included 40 male db/db diabetic and wild-type (WT) mice that were categorized into the following four groups at the age of 3 weeks: db/db group (DG), db/db+G-CSF group (DGG), WT group (WG), and WT+G-CSF group (WGG)...
April 4, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28374166/a-randomized-controlled-trial-to-establish-effects-of-short-term-rapamycin-treatment-in-24-middle-aged-companion-dogs
#13
Silvan R Urfer, Tammi L Kaeberlein, Susan Mailheau, Philip J Bergman, Kate E Creevy, Daniel E L Promislow, Matt Kaeberlein
Age is the single greatest risk factor for most causes of morbidity and mortality in humans and their companion animals. As opposed to other model organisms used to study aging, dogs share the human environment, are subject to similar risk factors, receive comparable medical care, and develop many of the same age-related diseases humans do. In this study, 24 middle-aged healthy dogs received either placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. All dogs received clinical and hematological exams before, during, and after the trial and echocardiography before and after the trial...
April 3, 2017: GeroScience
https://www.readbyqxmd.com/read/28371119/rapamycin-inhibits-the-secretory-phenotype-of-senescent-cells-by-a-nrf2-independent-mechanism
#14
Rong Wang, Zhen Yu, Bharath Sunchu, James Shoaf, Ivana Dang, Stephanie Zhao, Kelsey Caples, Lynda Bradley, Laura M Beaver, Emily Ho, Christiane V Löhr, Viviana I Perez
Senescent cells contribute to age-related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. In wild-type (WT) mouse fibroblasts, rapamycin increased the levels of Nrf2, and this correlates with the activation of autophagy and a reduction in the induction of cell senescence, as measured by SA-β-galactosidase (β-gal) staining, senescence-associated secretory phenotype (SASP), and p16 and p21 molecular markers...
March 31, 2017: Aging Cell
https://www.readbyqxmd.com/read/28358805/fasting-regulates-egr1-and-protects-from-glucose-and-dexamethasone-dependent-sensitization-to-chemotherapy
#15
Stefano Di Biase, Hong Seok Shim, Kyung Hwa Kim, Manlio Vinciguerra, Francesca Rappa, Min Wei, Sebastian Brandhorst, Francesco Cappello, Hamed Mirzaei, Changhan Lee, Valter D Longo
Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone...
March 2017: PLoS Biology
https://www.readbyqxmd.com/read/28351423/epigenetic-aging-signatures-in-mice-livers-are-slowed-by-dwarfism-calorie-restriction-and-rapamycin-treatment
#16
Tina Wang, Brian Tsui, Jason F Kreisberg, Neil A Robertson, Andrew M Gross, Michael Ku Yu, Hannah Carter, Holly M Brown-Borg, Peter D Adams, Trey Ideker
BACKGROUND: Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. RESULTS: We first examined whether mice and humans experience similar patterns of change in the methylome with age...
March 28, 2017: Genome Biology
https://www.readbyqxmd.com/read/28351383/diverse-interventions-that-extend-mouse-lifespan-suppress-shared-age-associated-epigenetic-changes-at-critical-gene-regulatory-regions
#17
John J Cole, Neil A Robertson, Mohammed Iqbal Rather, John P Thomson, Tony McBryan, Duncan Sproul, Tina Wang, Claire Brock, William Clark, Trey Ideker, Richard R Meehan, Richard A Miller, Holly M Brown-Borg, Peter D Adams
BACKGROUND: Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 (df/df) mutation, calorie restriction and rapamycin...
March 28, 2017: Genome Biology
https://www.readbyqxmd.com/read/28347844/complex-inhibition-of-autophagy-by-mitochondrial-aldehyde-dehydrogenase-shortens-lifespan-and-exacerbates-cardiac-aging
#18
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/28341273/branched-chain-amino-acids-enhance-cyst-development-in-autosomal-dominant-polycystic-kidney-disease
#19
Junya Yamamoto, Saori Nishio, Fumihiko Hattanda, Daigo Nakazawa, Toru Kimura, Michio Sata, Minoru Makita, Yasunobu Ishikawa, Tatsuya Atsumi
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1(flox/flox):Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid-induced conditional Pkd1 knockout at two weeks of age...
March 21, 2017: Kidney International
https://www.readbyqxmd.com/read/28340042/effects-of-dietary-l-arginine-levels-on-small-intestine-protein-turnover-and-the-expression-of-genes-related-to-protein-synthesis-and-proteolysis-of-layers
#20
L P Miao, C Yuan, X Y Dong, X Y Zhang, M Y Zhou, X T Zou
The aim of this study was to test the effects of dietary L-arginine (Arg) levels on protein turnover in the small intestine and the expression of genes related to protein synthesis and proteolysis of laying hens. Xinyang Black commercial laying hens (n = 864, aged 217 d) were randomly distributed to 6 treatments with 4 replicates of 36 birds. The dietary treatments were corn-corn gluten meal based diets containing 0.64, 0.86, 1.03, 1.27, 1.42 and 1.66% L-Arg, respectively. Fractional protein synthesis rate (FSR) and fractional protein gain rate (FGR) in the jejunum were the highest in the 1...
March 9, 2017: Poultry Science
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