The role of quantitative ADME proteomics to support construction of physiologically based pharmacokinetic models for use in small molecule drug development

Pharmacokinetics (PK) refers to the time course of drug concentrations in the body and since knowledge of PK aids understanding of drug efficacy and safety, numerous PK studies are performed in animals and humans during the drug development process. In vitro to in vivo extrapolation and physiologically based pharmacokinetic (PBPK) modeling are tools that integrate data from various in silico, in vitro, and in vivo sources to deliver mechanistic quantitative simulations of in vivo PK. PBPK models are used to predict human PK and to evaluate the effects of intrinsic factors such as organ dysfunction, age, and genetics as well as extrinsic factors such as co-administered drugs. In recent years, the use of PBPK within the industry has greatly increased. However, insufficient data on how the abundance of metabolic enzymes and membrane transporters vary in different human patient populations and in different species has been a limitation. A major advance is therefore expected through reliable quantification of the abundance of these proteins in tissues. This review describes the role of PBPK modeling in drug discovery and development, outlines the assumptions involved in integrating protein abundance data, and describes the advances made and expected in determining abundance of relevant proteins through mass spectrometric techniques.     

Ultrasound-guided fine needle aspiration biopsy in the diagnosis of breast cancer recurrence after mastectomy

PURPOSE: To define the accuracy and clinical impact of fine needle aspiration biopsy (FNAB) in diagnosing recurrent breast cancer after mastectomy. MATERIAL AND METHODS: The results of ultrasonography (US) and US-guided FNAB of 175 lesions located at the mastectomy site or in the ipsilateral axilla were reviewed. The final diagnosis was recurrent cancer in 77 cases and benign lesion in 98 cases, as verified by histological examination (n = 77) or follow-up (n = 98). RESULTS: FNAB yielded a representative aspirate in 92.6% of cases. The sensitivity, specificity and overall accuracy of FNAB cytology were 96.1%, 89.8% and 92.6% respectively. US and FNAB cytology were complementary methods in recurrent cancer diagnosis. The cytologic examination increased the specificity of US. The only recurrent tumor which appeared benign both sonographically and cytologically was removed because of a suspicious finding at palpation. FNAB cytologic diagnosis was found to have a clinical impact in 92.2% of the recurrent cases. CONCLUSION: US-guided FNAB provided an accurate adjunct to clinical examination and mammography for diagnosing and excluding breast cancer recurrence after mastectomy.     

Analysis of short fibres orientation in steel fibre-reinforced concrete (SFRC) by X-ray tomography

The mechanical properties of fibre composite materials are largely determined by the orientation of fibres within the matrix. Which orientation distribution short fibres follow in different parts of a structural element is still a subject for research and discussions in the scientific community. In this article, we present a modern and advanced method for measuring the orientation of short fibres in steel fibre-reinforced concrete (SFRC) by X-ray microtomography. With this method, a voxel image of the fibres is obtained directly in 3D, and the orientation of each individual fibre is calculated based on a skeletonized representation of this image. Scans of 12 SFRC samples, taken from the central height region of real-size floor slabs, reveal the fibres to be mostly horizontally oriented near the centre of a floor slab and more vertically oriented near the edge; here the alignment with the formwork dominates. The fibre orientation distributions are characterized by several orientation parameters as quantitative measures for the alignment. On the practical side, this method has the potential to be incorporated into the development and production process of SFRC structures to verify how the fibres contribute to capacity.     

Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including γ-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)⁺ binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots.     

Softwood Distillate as a Bio-Based Additive in Wood-Plastic Composites

The possibility of using softwood distillate as a bio-based additive or filler in wood-plastic composites (WPCs) was studied by adding various amounts (1–20 wt%) of distillate to a commercial WPC consisting of thermally treated sawdust in a polypropylene (PP) matrix. Softwood distillate was obtained as a secondary product from industrial ThermoWood® processing and it was further processed in the laboratory. The addition of softwood distillate significantly enhanced the mechanical properties of WPC when the distillate content was 2 wt%; tensile strength increased by 5%, tensile modulus by 3%, flexural strength by 3%, and modulus of elasticity by almost 2% compared with the unmodified WPC. In addition, a considerable decrease (over 16%) in water absorption was observed on distillate addition. Proton-transfer-reaction time-of-flight mass-spectrometry (PTR-TOF-MS) analyses revealed that the addition of softwood distillate increased release rates of volatile organic compounds (VOCs) in general, and that the odor of acetaldehyde and guaiacol is detectable in several WPCs. Overall, softwood distillate had positive effects on this particular WPC.     

Dynamic and perturbative system analysis of granular material in a vibrating screen

In most particulate classification systems, feed rates in excess of 80% of the designed capacity leads to inefficiency and conversely feed rates below this value significantly diminishes the operational efficiencies. It therefore implies that maximum efficiency is only attainable at the expense of low capacity, and vice versa. This problem is caused by transience in granular flow due to start-ups and fluctuating feed-rates, in addition to fluctuations in feed material properties. If these variations are not checked, they cause instabilities, resulting in chaotic saddles responsible for in-process systemic error generation. These errors produce intermittent disruptions in production process and control. We have applied perturbation theory to study the effects of infinitesimal changes on the material balance analysis of the unit operation. The problem was identified as one of the highly multi-stable dynamic systems, characterized by ‘predator-prey’ phenomenon in dynamical systems theory. The study allowed formulation of optimal state equations, whose numerical solutions resulted in establishment of optimal operating conditions required to sustain stability, and consistently high tonnages and efficiency up to 99% simultaneously. The study also led to development of an optimization algorithm, which upon validation with experimental data showed a close relationship, with a minimal absolute error of 0.8 and a relative error of 6%. Finally, a representative case study was conducted on screen dimensioning, based on the determined parameters. Successful evolution of this methodology may be applied for up-scaling of real systems in future.     

Evaluation of a participatory ergonomic intervention process in kitchen work

We evaluated a participatory ergonomic intervention process applied in 59 municipal kitchens. In groups of three to five kitchens, the workers participated in eight workshops, and generated and evaluated solutions to optimize musculoskeletal load in their work. An ergonomist initiated and supported the process. By the end, 402 changes were implemented. Evaluative data were collected using research diaries, questionnaires, and focus group interviews. The intervention model proved feasible and the participatory approach was mostly experienced as motivating. The workers’ knowledge and awareness of ergonomics increased, which improved their ability to tackle ergonomic problems by themselves. The changes in ergonomics were perceived to decrease physical load and improve musculoskeletal health. As hindering factors for implementation, lack of time and motivation, and insufficient financial resources were mentioned. In addition, the workers expressed a wish for more support from the management, technical staff, and ergonomists.