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Pharmacometric modeling can capture tumor growth inhibition (TGI) dynamics and variability. These approaches do not usually consider covariates in high‐dimensional settings, whereas high‐dimensional molecular profiling technologies (“omics”) are being increasingly considered for prediction of anticancer drug treatment response. Machine learning (ML) approaches have been applied to identify high‐dimensional omics predictors for treatment outcome. Here, we aimed to combine TGI modeling and ML approaches for two distinct aims: omics‐based prediction of tumor growth profiles and identification of pathways associated with treatment response and resistance. We propose a two‐step approach combining ML using least absolute shrinkage and selection operator (LASSO) regression with pharmacometric modeling. We demonstrate our workflow using a previously published dataset consisting of 4706 tumor growth profiles of patient‐derived xenograft (PDX) models treated with a variety of mono‐ and combination regimens. Pharmacometric TGI models were fit to the tumor growth profiles. The obtained empirical Bayes estimates‐derived TGI parameter values were regressed using the LASSO on high‐dimensional genomic copy number variation data, which contained over 20,000 variables. The predictive model was able to decrease median prediction error by 4% as compared with a model without any genomic information. A total of 74 pathways were identified as related to treatment response or resistance development by LASSO, of which part was verified by literature. In conclusion, we demonstrate how the combined use of ML and pharmacometric modeling can be used to gain pharmacological understanding in genomic factors driving variation in treatment response.

Although the aldosterone/renin ratio (ARR) is the preferred screening test for primary aldosteronism (PA), patients with non-suppressed renin and a falsely negative ARR on non-interfering medications have occasionally been reported. This report describes the clinical characteristics and outcomes of seven patients with proven aldosterone-producing adenoma (APA) and non-suppressed renin. Chart review of seven PA patients with an APA and a non-suppressed plasma renin concentration (PRC > 8.4 mU/L) was undertaken to collect data on anthropometric and biochemical characteristics, diagnostic evaluation and postsurgical outcomes. Seven patients (two women and five men) with a proven APA had median (range) PRC, plasma aldosterone and ARR of 20 (9–43) mU/L, 750 (270–1940) pmol/L and 45 (8–62, normal

The first aim of this work was to study the solid-state copolymerization (SSP) of bis(2-hydroxyethyl)terephthalate (BHET) with poly(butylene terephthalate) (PBT) by FTIR spectroscopy. The development of the chemical microstructure during the SSP-reaction was examined as a function of the BHET content, showing the different regimes. The thermal behaviour of the resulting copolymers with different BHET contents was also investigated during cooling using infra-red dynamic spectra. For low BHET-concentrations, only crystallization of PBT-sequences was observed, while for high BHET-concentrations, only crystallization of PET-sequences was detectable with a cross-over behaviour for intermediate concentrations.

Incorporation of 2,2-bis[4-(2-hydroxyethoxy)phenyl]propane (Dianol 220 (R)) into poly(butylene terephthalate) (PBT) via solid-state copolymerization (SSP) showed that Dianol, besides being the reactant, also acts as a swelling agent for rigid amorphous PBT chain segments. Being swollen, these amorphous chain segments become sufficiently mobile to contribute to the SSP process. The thermal behavior of the resulting copolyesters is comparable with melt copolymerized copolymers, although having a different chemical microstructure. The main reason is a full miscibility in the melt of unmodified PBT chain segments and modified chain segments, which eliminates the advantages of a blocky microstructure for the SSP copolyesters. However, incorporation of 2,2'-biphenyldimethanol (BDM) into PBT resulted in a higher crystallization temperature compared with PBT-Dianol copolymers of equal composition. Preordering of polymer chains in the melt by incorporating rigid, phase separating BDM-moieties, preferably via SSP to obtain a non-random distribution, may be the origin of the enhanced crystallization temperature. (C) 2008 Wiley Periodicals, Inc.

To increase the T-g in combination with a retained crystallization rate, bis(2-hydroxyethyl)terephthalate (BHET) was incorporated into poly(butylene terephthalate) (PBT) via solid-state copolymerization (SSP). The incorporated BHET fraction depends on the miscibility of BHET in the amorphous phase of PBT prior to SSR DSC measurements showed that BHET is only partially miscible. During SSP, the miscible BHET fraction reacts via transesterification reactions with the mobile amorphous PBT segments. The immiscible BHET fraction reacts by self-condensation, resulting in the formation of poly(ethylene terephthalate) (PET) homopolymer. H-1-NMR sequence distribution analysis showed that self-condensation of BHET proceeded faster than the transesterification with PBT. SAXS measurements showed an increase in the long period with increasing fraction BHET present in the mixtures used for SSP followed by a decrease due to the formation of small PET crystals. DSC confirmed the presence of separate PET crystals. Furthermore, the incorporation of BHET via SSP resulted in PBT-PET copolymers with an increased T-g compared to PBT. However, these copolymers showed a poorer crystallization behavior. The modified copolymer chain segments are apparently fully miscible with the unmodified PBT chains in the molten state. Consequently, the crystal growth process is retarded resulting in a decreased crystallization rate and crystallinity. (c) 2007 Wiley Periodicals, Inc.

Two diols, 2,2-bis(4-[hydroxyethoxy]phenyl)propane (Dianol 220 (R)) and bis(2-hydroxyethyl)terephthalate (BHET), were incorporated into poly(butylene terephthalate) (PBT) by solid-state polymerization (SSP) and melt polymerization (MP). Different PBT/diol ratios were used to obtain copolymers with different compositions. C-13 NMR spectroscopy was used to analyze the sequence distribution and the data analysis was discussed in detail. Both Dianol and BHET were randomly incorporated in the MP copolymers. For both PBT-Dianol and PBT-BHET copolymers obtained via SSP, a non-random, blocky microstructure was obtained. For the PBT-Dianol copolymers, the randomness increased for increased fractions of incorporated Dianol. For the PBT-BHET copolymers, the randomness continuously decreased with increased fractions of incorporated BHET. (c) 2005 Elsevier B.V. All rights reserved.

The kinetics of the incorporation of an aromatic diol in poly(butylene terephthalate) (PBT) via solid-state polymerization (SSP) was studied. The selected diol was 2,2-bis[4-(2-hydroxyethoxy)phenyl]-propane (Dianol 220). Mixtures consisting of 85 mol % PBT and 15 mol % Dianol were isothermally polymerized in the solid-state at 180 degrees C while the polymerization time was varied. Combining HPLC and H-1 NMR spectroscopy results showed that Dianol monomer reacts with PBT via two consecutive first-order reactions, the Dianol monoester being an intermediate and fully incorporated Dianol as the final product. The two corresponding reaction rate constants were determined by fitting the first-order equations with experimental data, revealing that free Dianol monomer is more reactive toward transesterification with PBT than its monoester. Dianol was fully incorporated in PBT after a reaction time of 4 h. This result was confirmed by C-13 NMR sequence distribution analysis. SEC measurements showed that the molecular weight and polydispersity first decrease during the SSP reaction due to chain scission of PBT. The subsequent recombination of polymer chains after complete incorporation of all Dianol monomer leads to a buildup of the molecular weight resulting in high molecular weight copolymers.

Carboxylic acid end groups of poly(butylene terephalate) (PBT) granules were modified with an excess of 1,2-epoxybutane in supercritical CO 2 and in supercritical and subcritical mixtures of CO 2 with 10 mol% 1,4-dioxane. Temperatures of 120 and 180 °C and pressures of 60, 150 and 300 bar were applied. Best results were obtained for the modification in scCO 2 containing 10 mol% 1,4-dioxane at 180 °C. The carboxylic acid end group concentration was reduced from 44 mmol/kg to approximately 10 mmol/kg, which resulted in a significantly enhanced hydrolytic stability. This was demonstrated by measuring, both for unmodified and for 1,2-epoxybutane blocked PBT, the intrinsic viscosity as a function of hydrolysis time as well as the number and weight average molecular weights ( M n and M w ) before and after hydrolysis. After the modification, some PBT granules appeared more brittle than the unmodified PBT granules. The crystallinity proved to be enhanced by the plasticising effect of CO 2 /1,4-dioxane at 180 °C. No indications were obtained that the 1,2-epoxybutane modified end groups exhibit a nucleating effect on the PBT crystallisation.

People capture more and more photographs leading to large personal photo collections that require much time and effort to organize. A lack of organization can have a negative effect on photo retrieval and photo sharing. In this user-centred design case study, we have explored new possibilities for organizing and sharing photographs. To organize photographs, the concept living media was created; automatic positive selection based on which photographs are viewed more often and viewed for a longer time. These photographs are apparently more interesting, and therefore, they will keep their appearance; less popular photographs will slowly fade to black over time. To share living media away from the computer, the device Pearl was designed. Pearl has an integrated pico projector that projects an interactive collage of living media in a living room. Interaction with the collage, such as deleting unwanted photographs from the collage, gives input to the selection procedure of living media. Placing Pearl at a distance creates a larger projection size, suitable for sharing photographs with a group of people. Our design is evaluated in two small-user studies, where we found benefits and challenges of using a combination of positive selection and pico projectors for photowork and photo sharing.

The chemical microstructure of poly(butylene terephthalate) (PBT) copolymers obtained by incorporation of a rigid diol, 2,2-bis [4-(2-hydroxyethoxy)phenyl] propane (Dianol 220), into PBT using solid-state polymerization (SSP) and melt polymerization (MP) was analyzed. C-13 NMR sequence distribution analysis showed that Dianol was randomly incorporated in the PBT-Dianol copolymers obtained by MP. However, the used C-13 NMR sequence distribution analysis method was based on solution NMR. As a consequence, the obtained chemical microstructure reflects both the crystalline and amorphous part. For PBT-Dianol copolymers obtained by SSP, the modification only took place in the amorphous phase of PBT. Hence, knowledge of the chemical microstructure of the amorphous phase is important for tailoring the final properties of these copolymers obtained by SSP. Therefore, a calculation method was developed to adjust the solution C-13 NMR peak integral values of the dyad sequences in such a way that only the amorphous fraction, which participates in the transesterification process, was taken into consideration for calculating the degree of randomness. The semicrystalline PBT-Dianol copolymers as obtained by SSP were initially represented by the often-used two-phase (crystalline/amorphous) model. The resulting chemical microstructure of the amorphous phase gave a strong indication that part of the amorphous phase was not accessible for incorporation of Dianol by SSP. Therefore, a three-phase (crystalline, rigid amorphous and mobile amorphous) model was used to represent the morphology of the PBT-Dianol copolymers. Crystalline, mobile amorphous, and rigid amorphous fractions were determined by DSC. Using this three-phase model, the calculation method showed that only the mobile amorphous fraction was accessible for incorporation of Dianol by SSP. At the used solid-state polymerization temperature of 180 degrees C, the PBT chains in the rigid amorphous and crystalline phase are not mobile enough to participate in the transesterification reaction. Furthermore, determination of the chemical microstructure of the mobile amorphous fraction showed that Dianol was fully randomly incorporated in this fraction.