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MYC Overexpression at the Protein and mRNA Level and Cancer Outcomes among Men Treated with Radical Prostatectomy for Prostate Cancer.
Pettersson, A, Gerke, T, Penney, KL, Lis, RT, Stack, EC, Pértega-Gomes, N, Zadra, G, Tyekucheva, S, Giovannucci, EL, Mucci, LA, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2018;(2):201-207
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Abstract
Background: The proto-oncogene MYC is implicated in prostate cancer progression. Whether MYC tumor expression at the protein or mRNA level is associated with poorer prognosis has not been well studied.Methods: We conducted a cohort study including 634 men from the Physicians' Health Study and Health Professionals Follow-up Study treated with radical prostatectomy for prostate cancer in 1983-2004 and followed up for a median of 13.7 years. MYC protein expression was evaluated using IHC, and we used Cox regression to calculate HRs and 95% confidence intervals (CIs) of its association with lethal prostate cancer (distant metastases/prostate cancer-related death). We assessed the association between MYC mRNA expression and lethal prostate cancer in a case-control study, including 113 lethal cases and 291 indolent controls.Results: MYC nuclear protein expression was present in 97% of tumors. MYC protein expression was positively correlated with tumor proliferation rate (r = 0.37; P < 0.001) and negatively correlated with apoptotic count (r = -0.17; P < 0.001). There were no significant associations between MYC protein expression and stage, grade, or PSA level at diagnosis. The multivariable HR for lethal prostate cancer among men in the top versus bottom quartile of MYC protein expression was 1.09 (95% CI, 0.50-2.35). There was no significant association between MYC mRNA expression and lethal prostate cancer.Conclusions: Neither MYC protein overexpression nor MYC mRNA overexpression are strong prognostic markers in men treated with radical prostatectomy for prostate cancer.Impact: This is the largest study to examine the prognostic role of MYC protein and mRNA expression in prostate cancer. Cancer Epidemiol Biomarkers Prev; 27(2); 201-7. ©2017 AACR.
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Ezetimibe increases intestinal expression of the LDL receptor gene in dyslipidaemic men with insulin resistance.
Drouin-Chartier, JP, Tremblay, AJ, Lemelin, V, Lépine, MC, Lamarche, B, Couture, P
Diabetes, obesity & metabolism. 2016;(12):1226-1235
Abstract
AIM: To gain further insight into intestinal cholesterol homeostasis in dyslipidaemic men with insulin resistance (IR) by examining the impact of treatment with ezetimibe on the expression of key genes involved in cholesterol synthesis and LDL receptor (R)-mediated uptake of lipoproteins. METHODS A total of 25 men with dyslipidaemia and IR were recruited to participate in this double-blind, randomized, crossover, placebo-controlled trial. Participants received 10 mg/day ezetimibe or placebo for periods of 12 weeks each. Intestinal gene expression was measured by quantitative PCR in duodenal biopsy samples collected by gastroduodenoscopy at the end of each treatment. RESULTS A total of 20 participants completed the protocol. Treatment with ezetimibe significantly increased intestinal LDLR (+16.2%; P = .01), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoAR; +14.0%; P = .04) and acetyl-Coenzyme A acetyltransferase 2 (ACAT-2) mRNA expression (+12.5%; P = .03). Changes in sterol regulatory element-binding transcription factor 2 (SREBP-2) expression were significantly correlated with changes in HMG-CoAR (r = 0.55; P < .05), ACAT-2 (r = 0.69; P < .001) and proprotein convertase substilisin/kexin type 9 (PCSK9) expression (r = 0.45; P < .05). CONCLUSIONS These results show that inhibition of intestinal cholesterol absorption by ezetimibe increases expression of the LDLR gene, supporting the concept that increased LDL clearance with ezetimibe treatment occurs not only in the liver but also in the small intestine.
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Fasting and exercise differentially regulate BDNF mRNA expression in human skeletal muscle.
Walsh, JJ, Edgett, BA, Tschakovsky, ME, Gurd, BJ
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2015;(1):96-8
Abstract
Brain-derived neurotrophic factor (BDNF) gene expression was measured in human skeletal muscle following 3 intensities of exercise and a 48-h fast. No change in BDNF mRNA was observed following exercise, while fasting upregulated BDNF by ∼ 3.5-fold. These changes were dissociated from changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) following exercise (+2- to 15-fold) and fasting (∼-25%). These results challenge our understanding of the response of BDNF to energetic stress and highlight the importance of future work in this area.
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Effect of Danzhijiangtang capsule on monocyte chemoattractant protein-1 mRNA expression in newly diagnosed diabetes subclinical vascular lesions.
Fang, ZH, Liu, Y, Bao, TT, Ni, YQ, Liu, J, Shi, GB, Wu, JP, Yang, JP, Zhang, H
World journal of gastroenterology. 2013;(19):2963-8
Abstract
AIM: To investigate the effect of Danzhijiangtang capsule (DJC) on monocyte chemoattractant protein-1 (MCP-1) mRNA expression in newly diagnosed type 2 diabetes mellitus (T2DM) subclinical vascular lesions. METHODS Sixty-two patients with newly diagnosed T2DM subclinical vascular lesions were randomly divided into a control group and treatment group of 31 cases each. Oral antidiabetic therapy with routine western medicine was conducted in both groups, and the treatment group was additionally treated with DJCs. The treatment course for both groups was 12 wk. Before and after treatment, the total efficiency and traditional Chinese medicine (TCM) syndrome score were calculated. The fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), fasting insulin (FINS), insulin resistance index (IRI), hemoglobin (Hb)A1c, blood lipids, and hemorheology indices were determined. In addition, the levels of vascular endothelial growth factors including thrombomodulin (TM), von Willebrand factor (vWF), P-selectin and MCP-1 mRNA were determined. RESULTS After 12 wk of treatment, the TCM syndrome score was significantly decreased compared to before treatment in both groups. After treatment, FPG, 2hPG, HbA1c, FINS, IRI, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, whole blood low shear specific viscosity, plasma specific viscosity, TM, vWF, P-selectin and MCP-1 mRNA were significantly improved compared to before treatment in both groups. After treatment, the total efficiency and TCM syndrome score in the treatment group were better than in the control group. FINS, IRI, whole blood high shear specific viscosity, plasma specific viscosity, TM, vWF, P-selectin and MCP-1 mRNA level in the treatment group were significantly reduced after treatment compared with control group. CONCLUSION DJCs are efficacious in supplementing qi, nourishing yin and invigorating blood circulation, and upregulate MCP-1 mRNA expression in patients with T2DM subclinical vascular lesions.
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Combined whole-body vibration, resistance exercise, and sustained vascular occlusion increases PGC-1α and VEGF mRNA abundances.
Item, F, Nocito, A, Thöny, S, Bächler, T, Boutellier, U, Wenger, RH, Toigo, M
European journal of applied physiology. 2013;(4):1081-90
Abstract
We previously reported that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion (vibroX) markedly improves cycling endurance capacity, increases capillary-to-fibre ratio and skeletal muscle oxidative enzyme activity in untrained young women. These findings are intriguing, since increases in oxidative muscle phenotype and endurance capacity are typically induced by endurance but not heavy resistance exercise. Here, we tested the hypothesis that vibroX activates genes associated with mitochondrial biogenesis and angiogenesis. Eight healthy, recreationally resistance-trained young men performed either vibroX or resistance exercise (RES) in a randomised, cross-over design. Needle biopsies (M. vastus lateralis) were obtained at rest and 3 h post-exercise. Changes in relative gene expression levels were assessed by real-time quantitative PCR. After vibroX, vascular endothelial growth factor and peroxisome proliferator-activated receptor-γ coactivator 1α mRNA abundances increased to 2- and 4.4-fold, respectively, but did not significantly change above resting values after RES. Other genes involved in mitochondrial biogenesis were not affected by either exercise modality. While vibroX increased the expression of hexokinase II, xanthine dehydrogenase, and manganese superoxide dismutase mRNA, there were no changes in these transcripts after RES. This study demonstrates that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion activates metabolic and angiogenic gene programs, which are usually activated after endurance but not resistance exercise. Thus, targeted modification of high load resistance exercise by vibration and vascular occlusion might represent a novel strategy to induce endurance-type muscle adaptations.
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High-intensity endurance training improves adiponectin mRNA and plasma concentrations.
Moghadasi, M, Mohebbi, H, Rahmani-Nia, F, Hassan-Nia, S, Noroozi, H, Pirooznia, N
European journal of applied physiology. 2012;(4):1207-14
Abstract
Adiponectin is an anti-inflammatory protein that reduced in obesity. Exercise training may reduce the adipose tissue (AT), although it is not well known whether exercise-induced change in AT, increases the adiponectin mRNA expression and plasma concentrations or not; therefore, the purpose of this study was to investigate the adiponectin mRNA and plasma concentrations in middle-aged men after 12 weeks high-intensity exercise training and after a week detraining. Sixteen sedentary overweight and obese middle-aged men (age 41.18 ± 6.1 years; ± SD) volunteered to participate in this study. The subjects were randomly assigned to training group (n = 8) or control group (n = 8). The training group performed endurance training 4 days a week for 12 weeks at an intensity corresponding to 75-80% individual maximum oxygen consumption for 45 min. After 12 weeks of training, subjects underwent a week of detraining. The results showed that the BMI as well as central and peripheral AT volume were decreased in the training group compared to the control group (P < 0.05). After 12 weeks, the training group resulted in a significant increase (P < 0.05) in the adiponectin gene expression in abdominal and gluteal subcutaneous AT when compared with the control group. The results showed that plasma adiponectin concentrations increased and insulin resistance decreased after training compared to the control group (P < 0.05). After a week of detraining, the variables were not changed significantly in the training group. In conclusion, high-intensity endurance training caused an increase adiponectin mRNA in obese middle-aged men.
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Matched work high-intensity interval and continuous running induce similar increases in PGC-1α mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle.
Bartlett, JD, Hwa Joo, C, Jeong, TS, Louhelainen, J, Cochran, AJ, Gibala, MJ, Gregson, W, Close, GL, Drust, B, Morton, JP
Journal of applied physiology (Bethesda, Md. : 1985). 2012;(7):1135-43
Abstract
The aim of the present study was to test the hypothesis that acute high-intensity interval (HIT) running induces greater activation of signaling pathways associated with mitochondrial biogenesis compared with moderate-intensity continuous (CONT) running matched for work done. In a repeated-measures design, 10 active men performed two running protocols consisting of HIT [6 × 3-min at 90% maximal oxygen consumption (Vo(2max)) interspersed with 3-min recovery periods at 50% Vo(2max) with a 7-min warm-up and cool-down period at 70% Vo(2max)] or CONT (50-min continuous running at 70% Vo(2max)). Both protocols were matched, therefore, for average intensity, duration, and distance run. Muscle biopsies (vastus lateralis) were obtained preexercise, postexercise, and 3 h postexercise. Muscle glycogen decreased (P < 0.05) similarly in HIT and CONT (116 ± 11 vs. 111 ± 17 mmol/kg dry wt, respectively). Phosphorylation (P-) of p38MAPK(Thr180/Tyr182) (1.9 ± 0.1- vs. 1.5 ± 0.2-fold) and AMPK(Thr172) (1.5 ± 0.3- vs. 1.5 ± 0.1-fold) increased immediately postexercise (P < 0.05) in HIT and CONT, respectively, and returned to basal levels at 3 h postexercise. P-p53(Ser15) (HIT, 2.7 ± 0.8-fold; CONT, 2.1 ± 0.8-fold), PGC-1α mRNA (HIT, 4.2 ± 1.7-fold; CONT, 4.5 ± 0.9-fold) and HSP72 mRNA (HIT, 4.4 ± 2-fold; CONT, 3.5 ± 1-fold) all increased 3 h postexercise (P < 0.05) although neither parameter increased (P > 0.05) immediately postexercise. There was no difference between trials for any of the above signaling or gene expression responses (P > 0.05). We provide novel data by demonstrating that acute HIT and CONT running (when matched for average intensity, duration, and work done) induces similar activation of molecular signaling pathways associated with regulation of mitochondrial biogenesis. Furthermore, this is the first report of contraction-induced p53 phosphorylation in human skeletal muscle, thus highlighting an additional pathway by which exercise may initiate mitochondrial biogenesis.
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Noninvasive detection of candidate molecular biomarkers in subjects with a history of insulin resistance and colorectal adenomas.
Zhao, C, Ivanov, I, Dougherty, ER, Hartman, TJ, Lanza, E, Bobe, G, Colburn, NH, Lupton, JR, Davidson, LA, Chapkin, RS
Cancer prevention research (Philadelphia, Pa.). 2009;(6):590-7
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Abstract
We have developed novel molecular methods using a stool sample, which contains intact sloughed colon cells, to quantify colonic gene expression profiles. In this study, our goal was to identify diagnostic gene sets (combinations) for the noninvasive classification of different phenotypes. For this purpose, the effects of a legume-enriched, low glycemic index, high fermentable fiber diet was evaluated in subjects with four possible combinations of risk factors, including insulin resistance and a history of adenomatous polyps. In a randomized crossover design controlled feeding study, each participant (a total of 23; 5-12 per group) consumed the experimental diet (1.5 cups of cooked dry beans) and a control diet (isocaloric average American diet) for 4 weeks with a 3-week washout period between diets. Using prior biological knowledge, the complexity of feature selection was reduced to perform an exhaustive search on all allowable feature (gene) sets of size 3, and among these, 27 had (unbiased) error estimates of 0.15 or less. Linear discriminant analysis was successfully used to identify the best single genes and two- to three-gene combinations for distinguishing subjects with insulin resistance, a history of polyps, or exposure to a chemoprotective legume-rich diet. These results support our premise that gene products (RNA) isolated from stool have diagnostic value in terms of assessing colon cancer risk.
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Moisturizers change the mRNA expression of enzymes synthesizing skin barrier lipids.
Buraczewska, I, Berne, B, Lindberg, M, Lodén, M, Törmä, H
Archives of dermatological research. 2009;(8):587-94
Abstract
In a previous study, 7-week treatment of normal human skin with two test moisturizers, Complex cream and Hydrocarbon cream, was shown to affect mRNA expression of certain genes involved in keratinocyte differentiation. Moreover, the treatment altered transepidermal water loss (TEWL) in opposite directions. In the present study, the mRNA expression of genes important for formation of barrier lipids, i.e., cholesterol, free fatty acids and ceramides, was examined. Treatment with Hydrocarbon cream, which increased TEWL, also elevated the gene expression of GBA, SPTLC2, SMPD1, ALOX12B, ALOXE3, and HMGCS1. In addition, the expression of PPARG was decreased. On the other hand, Complex cream, which decreased TEWL, induced only the expression of PPARG, although not confirmed at the protein level. Furthermore, in the untreated skin, a correlation between the mRNA expression of PPARG and ACACB, and TEWL was found, suggesting that these genes are important for the skin barrier homeostasis. The observed changes further demonstrate that long-term treatment with certain moisturizers may induce dysfunctional skin barrier, and as a consequence several signaling pathways are altered.
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Rapid exercise-induced changes in PGC-1alpha mRNA and protein in human skeletal muscle.
Mathai, AS, Bonen, A, Benton, CR, Robinson, DL, Graham, TE
Journal of applied physiology (Bethesda, Md. : 1985). 2008;(4):1098-105
Abstract
The mRNA of the nuclear coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) increases during prolonged exercise and is influenced by carbohydrate availability. It is unknown if the increases in mRNA reflect the PGC-1alpha protein or if glycogen stores are an important regulator. Seven male subjects [23 +/- 1.3 yr old, maximum oxygen uptake (Vo(2 max)) 48.4 +/- 0.8 ml.kg(-1).min(-1)] exercised to exhaustion ( approximately 2 h) at 65% Vo(2 max) followed by ingestion of either a high-carbohydrate (HC) or low-carbohydrate (LC) diet (7 or 2.9 g.kg(-1).day(-1), respectively) for 52 h of recovery. Glycogen remained depressed in LC (P < 0.05) while returning to resting levels by 24 h in HC. PGC-1alpha mRNA increased both at exhaustion (3-fold) and 2 h later (6.2-fold) (P < 0.05) but returned to rest levels by 24 h. PGC-1alpha protein increased (P < 0.05) 23% at exhaustion and remained elevated for at least 24 h (P < 0.05). While there was no direct treatment effect (HC vs. LC) for PGC-1alpha mRNA or protein, there was a linear relationship between the changes in glycogen and those in PGC-1alpha protein during exercise and recovery (r = -0.68, P < 0.05). In contrast, PGC-1beta did not increase with exercise but rather decreased (P < 0.05) below rest level at 24 and 52 h, and the decrease was greater (P < 0.05) in LC. PGC-1alpha protein content increased in prolonged exercise and remained upregulated for 24 h, but this could not have been predicted by the changes in mRNA. The beta-isoform declined rather than increasing, and this was greater when glycogen was not resynthesized to rest levels.