Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host ...immunosurveillance. This first-in-human phase I study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1.
Fifty-two patients with advanced solid malignancies were treated with epacadostat 50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily (BID) in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity.
One dose-limiting toxicity (DLT) occurred at the dose of 300 mg BID (grade 3, radiation pneumonitis); another DLT occurred at 400 mg BID (grade 3, fatigue). The most common adverse events in >20% of patients overall were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. Treatment produced significant dose-dependent reductions in plasma kynurenine levels and in the plasma kynurenine/tryptophan ratio at all doses and in all patients. Near maximal changes were observed at doses of ≥100 mg BID with >80% to 90% inhibition of IDO1 achieved throughout the dosing period. Although no objective responses were detected, stable disease lasting ≥16 weeks was observed in 7 of 52 patients.
Epacadostat was generally well tolerated, effectively normalized kynurenine levels, and produced maximal inhibition of IDO1 activity at doses of ≥100 mg BID. Studies investigating epacadostat in combination with other immunomodulatory drugs are ongoing.
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•KOH modified Ascophyllum nodosum seaweed hydrochar is an effective V(V) adsorbent;•Weak binding of V(V) to the hydrochar indicates a reversible adsorption process;•The impact of ...co-existing cations had negligible impact on uptake of V(V);•Desorption and re-adsorption results indicate reusable potential for V(V) recovery.
Vanadium exists as a mobile and toxic trace metal in many alkaline residue leachates. Its removal and recovery not only reduces a global environmental risk but is also critical to the emergence of innovative technologies and the circular economy. In parallel, the use of treated biomass feedstock is receiving increased attention as a low cost adsorbent for toxic metals in wastewater. This study investigated the adsorption of Vanadium (V) from aqueous solution by KOH modified seaweed (Ascophyllum nodosum) hydrochar (HCKOH). The results showed that HCKOH is an effective V(V) adsorbent, achieving maximum uptake of 12.3 mg g−1 at solution pH 4, 60 min contact time and temperature 293 K. The kinetics followed a pseudo second order model with film diffusion controlling the overall adsorption rate. The type I adsorption isotherm was well fitted to a Langmuir model (qm = 12.3 mg g-1, R2 = 0.970, RMSE = 0.66) and a thermodynamic study indicated that the V(V) adsorption was both exothermic and spontaneous. The low enthalpy change (-10.97 kJ mol−1) indicated a weak binding of V(V) to HCKOH pointing to the possibility of V recovery. The impact of co-existing cations on V(V) uptake was negligible for Na(I) and Ga (III) but was reduced slightly for Al(III). Desorption and re-adsorption results (3 cycles) indicated that HCKOH has reusable potential to remove and recover V(V) from waste leachates.
Adsorption studies were carried out on a red mud modified sawdust biochar material to assess its capacity in the removal of vanadium (V) from aqueous solution. In this study, a number of parameters ...which can potentially influence V(V) adsorption were investigated including equilibrium V(V) solution concentration, contact time for effective V(V) removal, temperature of the adsorption process, solution pH and ionic strength. The uptake of V(V) was shown to be heavily influenced by solution pH with maximum uptake (16.45 mg g−1) achieved in the pH range of 3.5 - 5.5. The adsorption process was best described by the Langmuir model. The kinetics of the adsorption process indicated that V(V) uptake occurred within 60 min of contact and that pseudo-second order kinetics best described the kinetics of the overall adsorption process. There was a clear increase in V(V) uptake with increasing temperature (range 293–343 K) indicating an endothermic adsorption process and the level of uptake remained largely unchanged at solution salt concentrations of up to 0.1 M NaCl and competing cation concentrations of up to 2000 mg L-1 of sodium and 200 mg L-1 aluminium. The relatively weak interaction between V(V) and the modified biochar surface may indicate a possibility of recovery of the bound V(V) and subsequent regeneration of the adsorbent.
MicroRNAs regulate diverse cellular processes and play an integral role in cancer pathogenesis. Genomic variation within miRNA target sites may therefore be important sources for genetic differences ...in cancer risk. To investigate this possibility, we mapped HapMap single nucleotide polymorphisms (SNP) to putative miRNA recognition sites within genes dysregulated in estrogen receptor-stratified breast tumors and used local linkage disequilibrium patterns to identify high-ranking SNPs in the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome-wide association study for further testing. Two SNPs, rs1970801 and rs11097457, scoring in the top 100 from the CGEMS study, were in strong linkage disequilibrium with rs1434536, an SNP that resides within a miR-125b target site in the 3' untranslated region of the bone morphogenic receptor type 1B (BMPR1B) gene encoding a transmembrane serine/threonine kinase. We validated the CGEMS association findings for rs1970801 in an independent cohort of admixture-corrected cases identified from families with multiple case histories. Subsequent association testing of rs1434536 for these cases and CGEMS controls with imputed genotypes supported the association. Furthermore, luciferase reporter assays and overexpression of miR-125b-mimics combined with quantitative reverse transcription-PCR showed that BMPR1B transcript is a direct target of miR-125b and that miR-125b differentially regulates the C and T alleles of rs1434536. These results suggest that allele-specific regulation of BMPR1B by miR-125b explains the observed disease risk. Our approach is general and can help identify and explain the mechanisms behind disease association for alleles that affect miRNA regulation.
Human gene therapy is currently seeing an increase in the use of plasmid (pDNA)-based vectors as a preferred choice of vehicle for delivery of the therapeutic gene into the body. In this regard, the ...environmental impacts of the waste streams from the possible industrial scale manufacture of pDNA require more detailed assessment. In this study, an initial assessment was made of the nutrient phosphorus (P) inputs to four fermentation processes recommended for the industrial scale production of pDNA for the purposes of gene therapy. Phosphorus inputs to each of the four selected fermentation processes ranged from approximately 60
mg
l
−1 up to 3000
mg
l
−1 in the fresh media. However, the spent media waste from each of the processes exhibited only a minor reduction in the phosphorus concentrations indicating minimal uptake of P by the microorganisms. This unutilised excess level of phosphorus nutrient within the waste streams poses a strong potential for environmental impact. Waste minimisation studies were undertaken on one model fermentation process with the aim of reducing unnecessary phosphorus input. An optimised media containing a 98% reduction in added P to the media was developed. This phosphorus-minimised media had little quantitative effect upon cell biomass produced and no effect upon the quantity or quality of pDNA produced, relative to the control media. The reduction in P requirement results in an overall cost savings of 12% per fermentation batch, would simplify subsequent wastewater treatment and would contribute to slowing the depletion rate of a valuable, finite natural resource.
A series of adsorption studies were carried out on a glycidyl methacrylate-modified cellulose material functionalised with imidazole (cellulose–g-GMA-imidazole) to assess its capacity towards the ...removal of Pb(II) ions from aqueous solution. The study sought to establish the effect of a number of parameters on the removal of Pb(II) ions from solution by the cellulose–g-GMA-imidazole. The effect of initial metal concentration, contact time and solution temperature on the removal of Pb(II) ions from solution by the cellulose–g-GMA-imidazole was assessed. Cellulose–g-GMA-imidazole sorbent showed an uptake of ca. 72 mg/g of Pb(II) ions from aqueous solution at 23°C. The adsorption process is best described by the Langmuir adsorption model and the thermodynamics of the process suggest that the binding process is exothermic. The kinetics of the adsorption process indicated that the uptake of Pb(II) ions occurred within 40 min and that pseudo-second-order kinetics best describe the overall adsorption process.
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