32 research outputs found
Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)
This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Aim: Recently we have observed differences in the ability of metformin and AICAR
to repress glucose production from hepatocytes using 8CPT-cAMP. Previous results
indicate that besides activating protein kinase A, 8CPT-modified cAMP analogues
suppress the Nitrobenzylthioinosine (NBMPR)-sensitive equilibrative nucleoside
transporter ENT1. We aimed to exploit 8CPT-cAMP, 8CPT-2-Methyl-O-cAMP and
NBMPR, which is highly selective for a high-affinity binding-site on ENT1, to
investigate the role of ENT1 in the liver specific glucose lowering properties of
AICAR and metformin.
Methods: Primary mouse hepatocytes were incubated with AICAR and metformin in
combination with cAMP analogues, glucagon, forskolin and NBMPR. Hepatocyte
glucose production (HGP), and AMPK signalling were measured and a uridine
uptake assay with supporting LC-MS was used to investigate nucleoside depletion
from medium by cells.
Results: AICAR and metformin increased AMPK pathway phosphorylation and
decreased HGP induced by dibutyryl cAMP and glucagon. HGP was also induced by
8CPT-cAMP, 8CPT-2-Methyl-O-cAMP and NBMPR; however, in each case this was
resistant to suppression by AICAR but not metformin. Cross-validation of tracer and
mass spectrometry studies indicates that 8CPT-cAMP, 8CPT-2-Methyl-O-cAMP and
NBMPR inhibited the effects of AICAR at least in part by impeding its uptake into
hepatocytes.
Conclusions: We report for the first time that suppression of ENT1 induces HGP.
ENT1 inhibition also impedes uptake and effects of AICAR but not metformin on
HGP. Further investigation of nucleoside transport may illuminate a better
understanding of how metformin and AICAR each regulate HGP.L.L. was supported by a Cunningham Trust PhD studentship awarded to G.R. and
C.B. G.R. acknowledges additional support from the MRC (MR/K012924/1). This
work was part-funded by a Tenovus Scotland grant to C.B, who is a recipient of a
Diabetes UK RD Lawrence Fellowship (13/0004647)
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Quantifying reliability uncertainty : a proof of concept.
This paper develops Classical and Bayesian methods for quantifying the uncertainty in reliability for a system of mixed series and parallel components for which both go/no-go and variables data are available. Classical methods focus on uncertainty due to sampling error. Bayesian methods can explore both sampling error and other knowledge-based uncertainties. To date, the reliability community has focused on qualitative statements about uncertainty because there was no consensus on how to quantify them. This paper provides a proof of concept that workable, meaningful quantification methods can be constructed. In addition, the application of the methods demonstrated that the results from the two fundamentally different approaches can be quite comparable. In both approaches, results are sensitive to the details of how one handles components for which no failures have been seen in relatively few tests
Association of Inpatient Glucose Measurements With Amputations in Patients Hospitalized With Acute Diabetic Foot
Pyrazine based Pt(II) bis-alkynyl organometallic complexes: Synthesis, characterization, and cytotoxic effect on A549 human lung carcinoma cells
Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117
Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m
/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications ( P < .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide ( P = .14 v azacitidine), and 27% for azacitidine plus vorinostat ( P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications