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Low-Dose Metformin Treatment Reduces In Vitro Growth of the LL/2 Non-small Cell Lung Cancer Cell Line
Lung cancer maintains a relatively small survival rate (~19%) over a 5-year period and up to 80–85% of all lung cancer diagnoses are Non-Small Cell Lung Cancer (NSCLC). To determine whether metformin reduces non-small cell lung cancer (NSCLC) LL/2 cell growth, cells were grown in vitro and treated with metformin for 48 h. qPCR was used to assess genes related to cell cycle regulation and pro-apoptotic markers, namely Cyclin D, CDK4, p27, p21, and HES1. Treatment with 10 mM metformin significantly reduced HES1 expression (p = 0.011). Furthermore, 10 mM metformin treatment significantly decreased REDD1 (p = 0.0082) and increased p-mTOR Ser2448 (p = 0.003) protein expression. Control cells showed significant reductions in phosphorylated p53 protein expression (p = 0.0367), whereas metformin treated cells exhibited reduced total p53 protein expression (p = 0.0078). There were no significant reductions in AMPK, PKB/AKT, or STAT3. In addition, NSCLC cells were treated for 48 h. with 10 mM metformin, 4 µM gamma-secretase inhibitor (GSI), or the combination of metformin (10 mM) and GSI (4 µM) to determine the contribution of respective signaling pathways. Metformin treatment significantly reduced total nucleus expression of the proliferation maker Ki-67 with an above 65% reduction in Ki-67 expression between control and metformin-treated cells (p = 0.0021). GSI (4 µM) treatment significantly reduced Ki-67 expression by ~20% over 48 h (p = 0.0028). Combination treatment (10 mM metformin and 4 µM GSI) significantly reduced Ki-67 expression by more than 50% over 48 h (p = 0.0245). As such, direct administration of metformin (10 mM for 48 h) proved to be an effective pharmaceutical agent in reducing the proliferation of cultured non-small cell cancer cells. These intriguing in vitro results, therefore, support the further study of metformin in appropriate in vivo models as an anti-oncogenic agent and/or an adjunctive therapy.
Journal Article
It came from Ohio! : my life as a writer
A portrait of the author of the Goosebumps series, shares insight into his childhood, education, and literary inspirations, with answers to frequently asked questions about his life, books, and writing style.
BOOK
Current Thoughts of Notch’s Role in Myoblast Regulation and Muscle-Associated Disease
The evolutionarily conserved signaling pathway Notch is unequivocally essential for embryogenesis. Notch’s contribution to the muscle repair process in adult tissue is complex and obscure but necessary. Notch integrates with other signals in a functional antagonist manner to direct myoblast activity and ultimately complete muscle repair. There is profound recent evidence describing plausible mechanisms of Notch in muscle repair. However, the story is not definitive as evidence is slowly emerging that negates Notch’s importance in myoblast proliferation. The purpose of this review article is to examine the prominent evidence and associated mechanisms of Notch’s contribution to the myogenic repair phases. In addition, we discuss the emerging roles of Notch in diseases associated with muscle atrophy. Understanding the mechanisms of Notch’s orchestration is useful for developing therapeutic targets for disease.
Journal Article
Survival associated with chronic obstructive pulmonary disease among SEER-Medicare beneficiaries with non-small-cell lung cancer
We investigated the impact of preexisting COPD and its subtypes, chronic bronchitis and emphysema, on overall survival among Medicare enrollees diagnosed with non-small-cell lung cancer (NSCLC).
Using SEER-Medicare data, we included patients ≥66 years of age diagnosed with NSCLC at any disease stage between 2006 and 2010 and continuously enrolled in Medicare Parts A and B in the 12 months prior to diagnosis. Preexisting COPD in patients with NSCLC were identified using ICD-9 codes. Kaplan-Meier method and log-rank tests were used to examine overall survival by COPD status and COPD subtype. Multivariable Cox proportional hazards models were fit to assess the risk of death after cancer diagnosis.
We identified 66,963 lung cancer patients. Of these, 22,497 (33.60%) had documented COPD before NSCLC diagnosis. For each stage of NSCLC, median survival was shorter in the COPD compared to the non-COPD group (Stage I: 692 days vs 1,130 days,
<0.0001; Stage II: 473 days vs 627 days,
<0.0001; Stage III: 224 days vs 229 days;
<0.0001; Stage IV: 106 days vs 112 days,
<0.0001). For COPD subtype, median survival for patients with preexisting chronic bronchitis was shorter compared to emphysema across all stages of NSCLC (Stage I: 672 days vs 811 days,
<0.0001; Stage II 582 days vs 445 days,
<0.0001; Stage III: 255 days vs 229 days,
<0.0001; Stage IV: 105 days vs 112 days,
<0.0001). In Cox proportional hazard model, COPD patients exhibited 11% increase in risk of death than non-COPD patients (HR: 1.11, 95%CI: 1.09-1.13).
NSCLC patients with preexisting COPD had shorter survival with marked differences in early stages of lung cancer. Chronic bronchitis demonstrated a greater association with time to death than emphysema.
Journal Article
Help your kids with geography : a unique step-by-step visual guide
\"Perplexed by plate tectonics? Confused by climates? Disorientated by demographics? Help Your Kids With Geography helps parents to get a grasp on what their children learn in geography class by exploring all these topics and more.\"--Publisher's description.
BOOK
Editorial: Emerging Mechanisms for Skeletal Muscle Mass Regulation
Skeletal muscle is considered an essential tissue involved in many physiological functions such as metabolism, thermoregulation, respiration, and locomotion. It has become clear that genetic and environmental factors are intricately involved in regulating skeletal muscle volume or myofiber size. The complexity of the orchestration of the signaling pathways that regulate these factors is intriguing. Muscle biologists strive to elucidate the myriad of signaling interactions critical for muscle volume and homeostasis. In this topic, we aimed to gain new insights into the basis of muscle volumetric and homeostatic regulation. We collected nine papers that embody novel or important concepts to skeletal myology. The three main areas compose the manuscripts: adult myogenesis, skeletal muscle mass regulation, and cancer-induced muscle weakness.
Journal Article
Phytoecdysteroids Do Not Have Anabolic Effects in Skeletal Muscle in Sedentary Aging Mice
Skeletal muscle mass and strength are lost with aging. Phytoecdysteroids, in particular 20-hydroxyecdysone (20E), increase protein synthesis in C2C12 skeletal muscle cells and muscle strength in young rats. The objective of this study was to determine whether an extract from Ajuga turkestanica (ATE), enriched in phytoecdysteroids, and 20E affect skeletal muscle mass and fiber size, fiber type, activation of the PI3K–Akt signaling pathway, and the mRNA levels of MAFbx, MuRF-1, and myostatin in sedentary aging mice. Aging male C57BL/6 mice (20 months old) received ATE, 20E, or vehicle (CT) once per day for 28 days or a single acute dose. Treatment did not alter body, muscle, or organ mass; fiber cross-sectional area; or fiber type in the triceps brachii or plantaris muscles. Likewise, protein synthesis signaling markers (i.e., phosphorylation of AktSer473 and p70S6kThr389) measured after either 28 days or acutely were unchanged. Neither ATE nor 20E treatment for 28 days affected the mRNA levels of MAFbx, MuRF-1, and myostatin. In conclusion, these data indicate that phytoecdysteroid treatment does not alter muscle mass or fiber type, nor does it activate protein synthesis signaling in the skeletal muscle of sedentary aging mice.
Journal Article
Notch Inhibition via GSI Treatment Elevates Protein Synthesis in C2C12 Myotubes
The role of Notch signaling is widely studied in skeletal muscle regeneration but little is known about its influences on muscle protein synthesis (MPS). The purpose of this study was to investigate whether Notch signaling is involved in the regulation of MPS. C2C12 cells were treated with a γ-secretase inhibitor (GSI), to determine the effect of reduced Notch signaling on MPS and anabolic signaling markers. GSI treatment increased myotube hypertrophy by increasing myonuclear accretion (nuclei/myotube: p = 0.01) and myonuclear domain (myotube area per fusing nuclei: p < 0.001) in differentiating C2C12 cells. GSI treatment also elevated myotube hypertrophy in differentiated C2C12s (area/myotube; p = 0.01). In concert, GSI treatment augmented pmTOR Ser2448 (p = 0.01) and protein synthesis (using SUnSET method) in myotubes (p < 0.001). Examining protein expression upstream of mTOR revealed reductions in PTEN (p = 0.04), with subsequent elevations in pAKT Thr308 (p < 0.001) and pAKT Ser473 (p = 0.05). These findings reveal that GSI treatment elevates myotube hypertrophy through both augmentation of fusion and MPS. This study sheds light on the potential multifaceted roles of Notch within skeletal muscle. Furthermore, we have demonstrated that Notch may modulate the PTEN/AKT/mTOR pathway.
Journal Article