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Oral Microbiota Profile Associates with Sugar Intake and Taste Preference Genes.
Esberg, A, Haworth, S, Hasslöf, P, Lif Holgerson, P, Johansson, I
Nutrients. 2020;(3)
Abstract
Oral microbiota ecology is influenced by environmental and host conditions, but few studies have evaluated associations between untargeted measures of the entire oral microbiome and potentially relevant environmental and host factors. This study aimed to identify salivary microbiota cluster groups using hierarchical cluster analyses (Wards method) based on 16S rRNA gene amplicon sequencing, and identify lifestyle and host factors which were associated with these groups. Group members (n = 175) were distinctly separated by microbiota profiles and differed in reported sucrose intake and allelic variation in the taste-preference-associated genes TAS1R1 (rs731024) and GNAT3 (rs2074673). Groups with higher sucrose intake were either characterized by a wide panel of species or phylotypes with fewer aciduric species, or by a narrower profile that included documented aciduric- and caries-associated species. The inferred functional profiles of the latter type were dominated by metabolic pathways associated with the carbohydrate metabolism with enrichment of glycosidase functions. In conclusion, this study supported in vivo associations between sugar intake and oral microbiota ecology, but it also found evidence for a variable microbiota response to sugar, highlighting the importance of modifying host factors and microbes beyond the commonly targeted acidogenic and acid-tolerant species. The results should be confirmed under controlled settings with comprehensive phenotypic and genotypic data.
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Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects.
Maekawa, Y, Furuie, H, Kato, M, Myobatake, Y, Kamiyama, E, Watanabe, A, Shiosakai, K, Taguchi, T, Bass, R, Zhou, J, et al
Clinical drug investigation. 2019;(10):967-978
Abstract
BACKGROUND Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER JapicCTI-152878.
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A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.
Moore, KN, Gunderson, CC, Sabbatini, P, McMeekin, DS, Mantia-Smaldone, G, Burger, RA, Morgan, MA, Kapoun, AM, Brachmann, RK, Stagg, R, et al
Gynecologic oncology. 2019;(2):294-301
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Abstract
OBJECTIVES The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P). RESULTS 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR). CONCLUSIONS IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.
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Efficacy and safety of the G protein-coupled receptor 119 agonist DS-8500a in Japanese type 2 diabetes mellitus patients with inadequate glycemic control on sitagliptin: A phase 2 randomized placebo-controlled study.
Terauchi, Y, Yamada, Y, Watada, H, Nakatsuka, Y, Shiosakai, K, Washio, T, Taguchi, T
Journal of diabetes investigation. 2018;(6):1333-1341
Abstract
INTRODUCTION We evaluated the efficacy and safety of DS-8500a as add-on therapy to sitagliptin in Japanese type 2 diabetes mellitus patients. MATERIALS AND METHODS This multicenter, randomized, double-blind, placebo-controlled, phase 2 trial randomized patients aged ≥20 years with hemoglobin A1c ≥7.0% and <9.0%, and inadequate glycemic control with sitagliptin 50-mg monotherapy to receive 25 or 75 mg DS-8500a, or a placebo, orally. The primary end-point was change from baseline to day 28 in 24-h weighted mean glucose. Secondary end-points included change from baseline in fasting plasma glucose, 2-h postprandial plasma glucose and lipid profiles. RESULTS Overall, 29, 28 and 27 patients in the placebo, 25- and 75-mg groups, respectively, were analyzed. A significant dose-dependent reduction was observed in 24-h weighted mean glucose (linear: P = 0.0006, saturated at 25 mg: P = 0.0003, responded from 75 mg: P = 0.0176) when compared with the placebo (25 mg: -13.19 mg/dL [-0.73 mmol/L], P = 0.0044 vs placebo and 75 mg: -16.12 mg/dL [-0.89 mmol/L], P = 0.0006 vs placebo). A significant reduction in fasting plasma glucose at 75 mg vs placebo was observed (P < 0.001). At 25 and 75 mg, significant reductions of 2-h postprandial plasma glucose (after breakfast), total cholesterol, low-cholesterol and triglycerides were observed (all P < 0.05), with a (non-significant) trend towards increased high-density lipoprotein cholesterol. Both doses of DS-8500a were well tolerated. There were no significant treatment-emergent adverse events leading to discontinuation during the study. CONCLUSIONS DS-8500a was well tolerated, and showed significant glycemic benefits and favorable changes in lipid profile in Japanese type 2 diabetes mellitus patients with inadequate glycemic control with sitagliptin therapy.
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Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial.
Kaku, K, Enya, K, Nakaya, R, Ohira, T, Matsuno, R
Diabetes, obesity & metabolism. 2015;(7):675-81
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Abstract
AIM: To assess the efficacy and safety of fasiglifam 25 and 50 mg in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. METHODS This phase III, double-blind, placebo-controlled, multicentre study included 192 patients randomized to once-daily treatment with fasiglifam 25 mg (n = 63) or 50 mg (n = 62) or placebo (n = 67) for 24 weeks. The primary efficacy endpoint was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS At week 24, both fasiglifam groups had significantly reduced HbA1c levels compared with the placebo group (p < 0.0001). The least squares mean change from baseline in HbA1c was 0.16% with placebo, -0.57% with fasiglifam 25 mg and -0.83% with fasiglifam 50 mg. The percentage of patients who achieved an HbA1c target of <6.9% at week 24 was also significantly higher (p < 0.05) for fasiglifam 25 mg (30.2%) and 50 mg (54.8%) compared with placebo (13.8%). Fasiglifam significantly reduced fasting plasma glucose levels at all assessment points, starting from week 2. The incidence and types of treatment-emergent adverse events in each fasiglifam group were similar to those in the placebo group, and hypoglycaemia was reported in 1 patient receiving fasiglifam 50 mg. There were no clinically meaningful changes in body weight in any treatment group. CONCLUSIONS Fasiglifam significantly improved glycaemic control and was well tolerated, with a low risk of hypoglycaemia in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise; however, in a recent review of data from overall fasiglifam global clinical trials, concerns about liver safety arose and the clinical development of fasiglifam was terminated after this trial was completed.
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G protein-coupled receptor 56 regulates matrix production and motility of lung fibroblasts.
Yang, J, Wang, Z, Leng, D, Dai, H, Wang, J, Liang, J, Jiang, D, Wang, C
Experimental biology and medicine (Maywood, N.J.). 2014;(6):686-96
Abstract
Idiopathic pulmonary fibrosis is a chronic, progressive, and fatal fibrotic lung disease with a poor prognosis, but no effective treatment is available. G protein-coupled receptor 56 (GPR56) plays a role in cell adhesion and tumor progression, but its function in fibrogenesis has not been explored. In this in vitro study, we found that GPR56 in IPF fibroblasts was lower than in normal fibroblasts. GPR56 regulated the production of fibronectin and type I collagen, and also changed the migratory and invasive capacity of lung fibroblasts. However, it was not sufficient to activate some classic markers of fibroblast and myofibroblast, such as α-smooth muscle actin and fibroblast specific protein 1. These findings demonstrate that reduced expression of GPR56 in lung fibroblasts may be an important link with pulmonary fibrosis, playing a role in regulating some important fibroblast functions.
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Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes.
Kaku, K, Araki, T, Yoshinaka, R
Diabetes care. 2013;(2):245-50
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OBJECTIVE Assessment of the efficacy and safety of TAK-875 (a novel GPR40 agonist) in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise. RESEARCH DESIGN AND METHODS This was a phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week dose-ranging evaluation of TAK-875 (6.25-200 mg once daily) with the primary end point of change in A1C at week 12. A nonblinded group received 1 mg glimepiride once daily as an active control. RESULTS A total of 396 patients were randomized to receive TAK-875 (n = 299), placebo (n = 48), or glimepiride (n = 49). The least square mean changes in A1C at week 12 from baseline were as follows: 0.09% in the placebo group; -0.54, -0.67, -0.88, -1.27, -1.29, and -1.40% in the 6.25-, 12.5-, 25-, 50-, 100-, and 200-mg TAK-875 groups, respectively; and -1.32% in the 1-mg glimepiride group. All TAK-875 groups had statistically significant reductions in A1C compared with placebo (P < 0.0001), and those receiving ≥50 mg TAK-875 achieved reductions in A1C equivalent to those with glimepiride. Results for other glycemic parameters, including improvements during a meal tolerance test, mirrored these positive findings with TAK-875. There were no significant differences in incidence of adverse events among the groups and no dose-dependent changes in tolerability. Hypoglycemic episodes were reported in 0.7% of patients in the TAK-875 groups and in 4.1% of the glimepiride group. CONCLUSIONS TAK-875 produced clinically and statistically significant improvements in glycemic control in patients with type 2 diabetes inadequately controlled by diet and exercise, and it was well tolerated with a lower propensity to cause hypoglycemia.
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GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes.
Araki, T, Hirayama, M, Hiroi, S, Kaku, K
Diabetes, obesity & metabolism. 2012;(3):271-8
Abstract
AIM: Free fatty acids act as signalling molecules for modulating insulin secretion, and their insulinotropic effects are glucose-dependent and mediated through G protein-coupled receptor 40 (GPR40). This mechanism is a potential target for new treatments for managing diabetes. In this study, we present the first clinical data for TAK-875, a novel highly selective, orally bioavailable GPR40 agonist, in Japanese patients with type 2 diabetes insufficiently controlled by diet or exercise therapy. METHODS This was an exploratory phase II, multicentre, randomized, double-blind, parallel group study comparing the efficacy and tolerability of TAK-875 100 and 400 mg, and placebo, all administered once daily for 2 weeks. RESULTS After 2 weeks of treatment, TAK-875 produced marked glucose lowering effects in a 75 g oral glucose tolerance test (OGTT) as evidenced by mean ± SE intergroup differences in plasma glucose AUC(0-3 h) of -12.98 ± 1.48 (p < 0.0001) and -8.12 ± 1.49 mmol·h/l (p < 0.0001), for TAK-875 400 mg vs. placebo and TAK-875 100 mg vs. placebo, respectively, and 2 h plasma glucose [-4.95 ± 0.71 (p < 0.0001) and -3.21 ± 0.71 mmol/l (p < 0.0001), respectively]. This was accompanied by a significant increase in insulin AUC(0-3 h) [34.68 ± 12.16 (p < 0.01) and 31.49 ± 12.20 (p < 0 · 05) µIU·h/ml, respectively]. Improvement in glycaemic profile was mirrored by a significant change in fasting plasma glucose [-2.37 ± 0·27 (p < 0.0001) and -1.88 ± 0.27 mmol/l (p < 0.0001), respectively]. No cases of hypoglycaemia were observed despite the significant reduction in plasma glucose. CONCLUSIONS These exploratory findings provide evidence of the glucose-dependent insulinotropic potential of the GPR40 agonist TAK-875, and the promising clinical changes support future longer term clinical investigation.
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Genomic, genetic and functional dissection of bitter taste responses to artificial sweeteners.
Roudnitzky, N, Bufe, B, Thalmann, S, Kuhn, C, Gunn, HC, Xing, C, Crider, BP, Behrens, M, Meyerhof, W, Wooding, SP
Human molecular genetics. 2011;(17):3437-49
Abstract
Bitter taste perception is initiated by TAS2R receptors, which respond to agonists by triggering depolarization of taste bud cells. Mutations in TAS2Rs are known to affect taste phenotypes by altering receptor function. Evidence that TAS2Rs overlap in ligand specificity suggests that they may also contribute joint effects. To explore this aspect of gustation, we examined bitter perception of saccharin and acesulfame K, widely used artificial sweeteners with aversive aftertastes. Both substances are agonists of TAS2R31 and -43, which belong to a five-member subfamily (TAS2R30-46) responsive to a diverse constellation of compounds. We analyzed sequence variation and linkage structure in the ∼140 kb genomic region encoding TAS2R30-46, taste responses to the two sweeteners in subjects, and functional characteristics of receptor alleles. Whole-gene sequences from TAS2R30-46 in 60 Caucasian subjects revealed extensive diversity including 34 missense mutations, two nonsense mutations and high-frequency copy-number variants. Thirty markers, including non-synonymous variants in all five genes, were associated (P< 0.001) with responses to saccharin and acesulfame K. However, linkage disequilibrium (LD) in the region was high (D', r(2) > 0.95). Haplotype analyses revealed that most associations were spurious, arising from LD with variants in TAS2R31. In vitro assays confirmed the functional importance of four TAS2R31 mutations, which had independent effects on receptor response. The existence of high LD spanning functionally distinct TAS2R loci predicts that bitter taste responses to many compounds will be strongly correlated even when they are mediated by different genes. Integrative approaches combining phenotypic, genetic and functional analysis will be essential in dissecting these complex relationships.
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Sensitivity of genome-wide-association signals to phenotyping strategy: the PROP-TAS2R38 taste association as a benchmark.
Genick, UK, Kutalik, Z, Ledda, M, Destito, MC, Souza, MM, Cirillo, CA, Godinot, N, Martin, N, Morya, E, Sameshima, K, et al
PloS one. 2011;(11):e27745
Abstract
Natural genetic variation can have a pronounced influence on human taste perception, which in turn may influence food preference and dietary choice. Genome-wide association studies represent a powerful tool to understand this influence. To help optimize the design of future genome-wide-association studies on human taste perception we have used the well-known TAS2R38-PROP association as a tool to determine the relative power and efficiency of different phenotyping and data-analysis strategies. The results show that the choice of both data collection and data processing schemes can have a very substantial impact on the power to detect genotypic variation that affects chemosensory perception. Based on these results we provide practical guidelines for the design of future GWAS studies on chemosensory phenotypes. Moreover, in addition to the TAS2R38 gene past studies have implicated a number of other genetic loci to affect taste sensitivity to PROP and the related bitter compound PTC. None of these other locations showed genome-wide significant associations in our study. To facilitate further, target-gene driven, studies on PROP taste perception we provide the genome-wide list of p-values for all SNPs genotyped in the current study.