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Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: data from FIRE-3 and TRIBE trials.
Berger, MD, Stintzing, S, Heinemann, V, Yang, D, Cao, S, Sunakawa, Y, Ning, Y, Matsusaka, S, Okazaki, S, Miyamoto, Y, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2017;(11):2780-2785
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Abstract
BACKGROUND The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). PATIENTS AND METHODS A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. RESULTS AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P = 0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P = 0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P = 0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P = 0.015) and multivariable analysis (HR 1.76, P = 0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P = 0.005). CONCLUSION MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.
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Genetic variants ofLRRK2 in Taiwanese Parkinson's disease.
Wu, YR, Chang, KH, Chang, WT, Hsiao, YC, Hsu, HC, Jiang, PR, Chen, YC, Chao, CY, Chang, YC, Lee, BH, et al
PloS one. 2013;(12):e82001
Abstract
Genetic variants of leucine-rich repeat kinase 2 (LRRK2) were reported to alter the risk for Parkinson's disease (PD). However, the genetic spectrum of LRRK2 variants has not been clearly disclosed yet in Taiwanese population. Herein, we sequenced LRRK2 coding region in 70 Taiwanese early onset PD patients (age at onset ≤ 50), and found six amino acid-changing single nucleotide polymorphisms (SNPs, N551K, R1398H, R1628P, S1647T, G2385R and M2397T), one reported (R1441H) and 2 novel missense (R767H and S885N) mutations. We examined the frequency of identified LRRK2 variants by genotyping 573 Taiwanese patients with PD and 503 age-matched control subjects. The results showed that PD patients demonstrated a higher frequency of G2385R A allele (4.6%) than control subjects (2.1%; odds ratio = 2.27, 95% confidence interval: 1.38-3.88, P = 0.0017). Fewer PD patients (27.7%) carried the 1647T-2397T haplotype as compared with the control subjects (33.0%; odds ratio = 0.80, 95% confidence interval: 0.65-0.97, P = 0.0215). However, the frequency of 1647T-2385R-2397T haplotype (4.3%) in PD patients was still higher than in control subjects (1.9%, odds ratio: 2.15, 95% confidence interval: 1.27-3.78, P = 0.0058). While no additional subject was found to carry R767H and R1441H, one more patient was observed to carry the S885N variant. Our results indicate a robust risk association regarding G2385R and a new possible protective haplotype (1647T-2397T). Gene-environmental interaction and a larger cohort study are warranted to validate our findings. Additionally, two new missense mutations (R767H and S885N) regarding LRRK2 in PD patients were identified. Functional studies are needed to elucidate the effects of these LRRK2 variants on protein function.
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Common variation in with no-lysine kinase 1 (WNK1) and blood pressure responses to dietary sodium or potassium interventions- family-based association study.
Liu, F, Zheng, S, Mu, J, Chu, C, Wang, L, Wang, Y, Xiao, H, Wang, D, Cao, Y, Ren, K, et al
Circulation journal : official journal of the Japanese Circulation Society. 2013;(1):169-74
Abstract
BACKGROUND Common variations in the gene with no-lysine kinase 1 (WNK1) are associated with hypertension, but because of gene-environment interaction, it is difficult to fully identify the genetic contribution of WNK1 gene polymorphism to blood pressure (BP) variability. The aim of this study was to identify the effect of common WNK1 variants on the shift of BP during strict dietary interventions of salt or potassium intake. METHODS AND RESULTS A total of 342 subjects from 126 families were selected and sequentially maintained on normal diet for 3 days at baseline, a low-salt diet for 7 days (3g/day, NaCl), then a high-salt diet for 7 days (18 g/day), and high-salt diet with potassium supplementation for another 7 days (4.5 g/day, KCl). Five single nucleotide polymorphisms (SNPs) were selected from the WNK1 gene. rs880054 and rs12828016 were associated with diastolic BP (DBP) response during the low-or high-sodium intervention, and rs2301880 was significantly associated with systolic BP, DBP and mean arterial pressure responses to the high-sodium intervention (all P<0.05). Unfortunately, no associations for WNK1 SNPs and the constructed haplotype blocks of WNK1 with BP responses to high-salt-and-potassium supplement intervention reached nominal statistical significance. CONCLUSIONS The WNK1 gene might be mechanistically involved in the variation in BP response to dietary sodium and potassium intake among individuals, and might contribute to the variation of this complex phenotype.
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Carbohydrate refeeding after a high-fat diet rapidly reverses the adaptive increase in human skeletal muscle PDH kinase activity.
Bigrigg, JK, Heigenhauser, GJ, Inglis, JG, LeBlanc, PJ, Peters, SJ
American journal of physiology. Regulatory, integrative and comparative physiology. 2009;(3):R885-91
Abstract
Pyruvate dehydrogenase (PDH) regulates oxidative carbohydrate disposal in skeletal muscle and is downregulated by reversible phosphorylation catalyzed by PDH kinase (PDK). Previous work has demonstrated increased PDK activity and PDK4 expression in human skeletal muscle following a high-fat low-carbohydrate (HF) diet, which leads to decreased PDH in the active form (PDHa activity) and carbohydrate oxidation. The purpose of this study was to examine the time course of changes in PDK and PDHa activities with refeeding of carbohydrates after an HF diet in human skeletal muscle. Healthy male volunteers (n = 8) consumed a standardized 3-day Pre-diet with the same energy content as their habitual diet, followed by a eucaloric 6-day HF diet (Pre-diet: 50:30:20%; HF diet: 5:75:20%; carbohydrate/fat/protein). Muscle biopsies were taken before and after the HF diet and at 45 min and 3 h after carbohydrate refeeding with a single high-glycemic index carbohydrate meal (88:5:7% carbohydrate/fat/protein) representing approximately one third of the individual subject's habitual energy intake. PDK activity increased from 0.08 +/- 0.01 Pre- to 0.25 +/- 0.02 min (P < 0.001) Post-HF diet, and decreased with carbohydrate refeeding to 0.17 +/- 0.05 (P = 0.014) and 0.11 +/- 0.01 min (P = 0.006) at 45 min and 3 h, respectively. PDHa decreased from 0.89 +/- 0.20 to 0.32 +/- 0.05 (P = 0.007) mmol x min(-1) x kg wet wt(-1) following the HF diet, and was increased transiently with refeeding at 45 min, but returned to lower values by 3 h (P = 0.025 compared with Pre). The potential mechanism(s) for this attenuation of PDHa activity remains unclear. These data demonstrate that in human skeletal muscle, the adaptive increase in PDK activity following an HF diet is rapidly reversed to Pre-diet activity levels within 45 min to 3 h, and this is accompanied by a short-term increase in PDHa activity.
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Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study.
Sriwijitkamol, A, Coletta, DK, Wajcberg, E, Balbontin, GB, Reyna, SM, Barrientes, J, Eagan, PA, Jenkinson, CP, Cersosimo, E, DeFronzo, RA, et al
Diabetes. 2007;(3):836-48
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Abstract
Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI approximately 25 kg/m(2)) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m(2)), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% Vo(2max)) and moderate (70% Vo(2max)) intensities, with a 4-6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects.
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Influence of muscle glycogen availability on ERK1/2 and Akt signaling after resistance exercise in human skeletal muscle.
Creer, A, Gallagher, P, Slivka, D, Jemiolo, B, Fink, W, Trappe, S
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(3):950-6
Abstract
Two pathways that have been implicated for cellular growth and development in response to muscle contraction are the extracellular signal-regulated kinase (ERK1/2) and Akt signaling pathways. Although these pathways are readily stimulated after exercise, little is known about how nutritional status may affect stimulation of these pathways in response to resistance exercise in human skeletal muscle. To investigate this, experienced cyclists performed 30 repetitions of knee extension exercise at 70% of one repetition maximum after a low (2%) or high (77%) carbohydrate (LCHO or HCHO) diet, which resulted in low or high (approximately 174 or approximately 591 mmol/kg dry wt) preexercise muscle glycogen content. Muscle biopsies were taken from the vastus lateralis before, approximately 20 s after, and 10 min after exercise. ERK1/2 and p90 ribosomal S6 kinase phosphorylation increased (P < or = 0.05) 10 min after exercise, regardless of muscle glycogen availability. Akt phosphorylation was elevated (P < 0.05) 10 min after exercise in the HCHO trial but was unaffected after exercise in the LCHO trial. Mammalian target of rapamycin phosphorylation was similar to that of Akt during each trial; however, change or lack of change was not significant. In conclusion, the ERK1/2 pathway appears to be unaffected by muscle glycogen content. However, muscle glycogen availability appears to contribute to regulation of the Akt pathway, which may influence cellular growth and adaptation in response to resistance exercise in a low-glycogen state.
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Short-term exercise training in humans reduces AMPK signalling during prolonged exercise independent of muscle glycogen.
McConell, GK, Lee-Young, RS, Chen, ZP, Stepto, NK, Huynh, NN, Stephens, TJ, Canny, BJ, Kemp, BE
The Journal of physiology. 2005;(Pt 2):665-76
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Abstract
We examined the effect of short-term exercise training on skeletal muscle AMP-activated protein kinase (AMPK) signalling and muscle metabolism during prolonged exercise in humans. Eight sedentary males completed 120 min of cycling at 66 +/- 1% , then exercise trained for 10 days, before repeating the exercise bout at the same absolute workload. Participants rested for 72 h before each trial while ingesting a high carbohydrate diet (HCHO). Exercise training significantly (P < 0.05) attenuated exercise-induced increases in skeletal muscle free AMP: ATP ratio and glucose disposal and increased fat oxidation. Exercise training abolished the 9-fold increase in AMPK alpha2 activity observed during pretraining exercise. Since training increased muscle glycogen content by 93 +/- 12% (P < 0.01), we conducted a second experiment in seven sedentary male participants where muscle glycogen content was essentially matched pre- and post-training by exercise and a low CHO diet (LCHO; post-training muscle glycogen 52 +/- 7% less than in HCHO, P < 0.001). Despite the difference in muscle glycogen levels in the two studies we obtained very similar results. In both studies the increase in ACCbeta Ser(221) phosphorylation was reduced during exercise after training. In conclusion, there is little activation of AMPK signalling during prolonged exercise following short-term exercise training suggesting that other factors are important in the regulation of glucose disposal and fat oxidation under these circumstances. It appears that muscle glycogen is not an important regulator of AMPK activation during exercise in humans when exercise is begun with normal or high muscle glycogen levels.
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Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm.
Mohri, M, Shimokawa, H, Hirakawa, Y, Masumoto, A, Takeshita, A
Journal of the American College of Cardiology. 2003;(1):15-9
Abstract
OBJECTIVES We sought to determine whether a potent Rho-kinase inhibitor fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm. BACKGROUND Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction. METHODS We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (ACh) induced myocardial ischemia (ischemic electrocardiographic changes, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second ACh challenge test after pretreatment with either saline (n = 5) or fasudil (4.5 mg intracoronarily, n = 13). RESULTS Myocardial ischemia was reproducibly induced by ACh in the saline group. In contrast, 11 of the 13 patients pretreated with fasudil had no evidence of myocardial ischemia during the second infusion of ACh (p < 0.01). The lactate extraction ratio (median value [interquartile range]) during ACh infusion was improved by fasudil pretreatment, from -0.16 (-0.25 to 0.04) to 0.09 (0.05 to 0.18) (p = 0.0125). CONCLUSIONS Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm. The inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.
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Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study.
Shimokawa, H, Hiramori, K, Iinuma, H, Hosoda, S, Kishida, H, Osada, H, Katagiri, T, Yamauchi, K, Yui, Y, Minamino, T, et al
Journal of cardiovascular pharmacology. 2002;(5):751-61
Abstract
Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.