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- In ’t Veld, Sjors G.J.G., et al.
(författare)
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Detection and localization of early- and late-stage cancers using platelet RNA
- 2022
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Ingår i: Cancer Cell. - : Elsevier. - 1535-6108 .- 1878-3686. ; 40:9, s. 999-1009.e6
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Tidskriftsartikel (refereegranskat)abstract
- Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.
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| 2. |
- Sinha, Vikash K., et al.
(författare)
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Towards a Better Prediction of Peak Concentration, Volume of Distribution and Half-Life after Oral Drug Administration in Man, Using Allometry
- 2011
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 50:5, s. 307-318
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Tidskriftsartikel (refereegranskat)abstract
- Background: it is imperative that new drugs demonstrate adequate pharmacokinetic properties, allowing an optimal safety margin and convenient dosing regimens in clinical practice, which then lead to better patient compliance. Such pharmacokinetic properties include suitable peak (maximum) plasma drug concentration (C-max), area under the plasma concentration-time curve (AUC) and a suitable half-life (t(1/4)). The C-max and t(1/2) following oral drug administration are functions of the oral clearance (CL/F) and apparent volume of distribution during the terminal phase by the oral route (V-z/F), each of which may be predicted and combined to estimate C-max and t(1/4). Allometric scaling is a widely used methodology in the pharmaceutical industry to predict human pharmacokinetic parameters such as clearance and volume of distribution. In our previous published work, we have evaluated the use of allometry for prediction of CL/F and AUC. In this paper we describe the evaluation of different allometric scaling approaches for the prediction of C-max, V-z/F and t(1/2) after oral drug administration in man. Methods: Twenty-nine compounds developed at Janssen Research and Development (a division of Janssen Pharmaceutica NV), covering a wide range of physicochemical and pharmacokinetic properties, were selected. The C,, following oral dosing of a compound was predicted using (i) simple allometry alone; (ii) simple allometry along with correction factors such as plasma protein binding (PPB), maximum life-span potential or brain weight (reverse rule of exponents, unbound C-max approach); and (iii) an indirect approach using allometrically predicted CL/F and V-z/F and absorption rate constant (k(a)). The k(a) was estimated from (i) in vivo pharmacokinetic experiments in preclinical species; and (ii) predicted effective permeability in man Weir), using a Caco-2 permeability assay. The V-z/F was predicted using allometric scaling with or without PPB correction. The t(1/2) was estimated from the allometrically predicted parameters CL/F and V-z/F. Predictions were deemed adequate when errors were within a 2-fold range. Results: C-max and t(1/2), could be predicted within a 2-fold error range for 59% and 66% of the tested compounds, respectively, using allometrically predicted CL/F and V-z/F. The best predictions for Cif, were obtained when K-a values were calculated from the Caco-2 permeability assay. The V-z/F was predicted within a 2-fold error range for 72% of compounds when PPB correction was applied as the correction factor for scaling. Conclusions: We conclude that (i) C-max and t(1/2), are best predicted by indirect scaling approaches (using allometrically predicted CL/F and V-z/F and accounting for ka derived from permeability assay); and (ii) the PPB is an important correction factor for the prediction of V-z/F by using allometric scaling. Furthermore, additional work is warranted to understand the mechanisms governing the processes underlying determination of C-max so that the empirical approaches can be fine-tuned further.
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