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• Utilized solution stability studies to identify the downstream process design space. • Evaluated excipients and solution components for their ability to expand design space. • Combination of excipient and elution salt modifications resulted in optimized process. • Solution stability method employed could be readily automated for all new molecules. • Solution stability from multiple molecules may enable development timeline acceleration. Platform manufacturing processes are widely adopted to simplify and standardize the development and manufacturing of monoclonal antibodies (mAbs). However, there are mAbs that do not conform to a platform design due to instability or other protein properties leading to a negative impact on product quality or process performance (non-platform mAb). Non-platform mAbs typically require prolonged development times and significant deviations from the platform process to address these issues due to the need to sequentially optimize individual process steps. In this study, we describe an IgG2 mAb (mAb A) that is susceptible to aggregation and reversible self-association (RSA) under platform conditions. In lieu of a sequential optimization approach, we evaluated the solution stability of mAb A across the platform operating space (solution stability screen). This screening design was used to identify interacting parameters that affected the non-platform mAb stability. A subsequent response surface design was found to predict an acceptable operating space that minimized aggregate formation and RSA across the entire process. This information guided the selection of optimal parameters best suited to avoid destabilizing conditions for each process step. Substantial time savings was achieved by focusing development around these factors including protein concentration, buffer pH, salt concentration, and excipient type. In addition, this work enabled the optimization of a cation exchange chromatography step that removed aggregate without yield losses due to the presence of reversible aggregation. The final optimized process derived from this study resulted in an increase in yield of ˜30% over the original process while maintaining the same level of aggregate clearance to match product quality. Solution stability screening is readily adapted to high throughput technologies to minimize material requirements and accelerate analytical data availability. Implementation of high throughput approaches will further expedite process development and enable enhanced selection of candidate drugs by including process development objectives. [ABSTRACT FROM AUTHOR]

This paper addresses the topic of transportation network vulnerability within the context of the New York City subway system. We propose a network model for it and an approach based on shortest-path passenger flow simulations in order to quantify delays experienced by passengers arising from disruptive events, particularly from those that occur simultaneously. We determine if and to what extent the effect under such simultaneous scenarios is greater than it would be had the same disruptions occurred as separate events. Our findings can be useful in supporting the planning decisions necessary to prepare for the harmful consequences arising from disruptions to complex urban networks. [ABSTRACT FROM AUTHOR]

A decrease in the expression of HLA antigens is considered a characteristic of tumor progression and is considered an important tumor-escape mechanism. In general, HLA Class I expression is even further decreased on metastases. Tumor cells that loose their HLA Class I antigens become less susceptible to lysis by specific T cells, but may become more sensitive to Natural Killer cells. Loss of HLA Class I can be observed at different levels, i.e. total loss of Class I, loss of expression of one locus or one haplotype, or even one specific allele. We studied HLA expression on human uveal melanoma and observed that loss of expression of a locus or one or more alleles is a common phenomenon. However, in contrast with the commonly accepted paradigm, loss of HLA Class I expression on the uveal melanoma was not associated with tumor cell escape and a worse survival, but with a better survival of the patients involved. We hypothesize that this is due to the route of metastases formation: in uveal melanoma, spreading of metastases is purely hematogeneous, and it is quite possible that NK-cell mediated surveillance of tumor cells in the blood is the underlying mechanism. This is supported by our finding that metastases of uveal melanoma have a high HLA Class I expression, leading to our conclusion that uveal melanoma is an exception to the general rule regarding HLA Class I expression in tumor immunology. [Copyright &y& Elsevier]

Selective serotonin reuptake inhibitors (SSRI) are commonly used to treat depression during pregnancy. SSRIs cross the placenta and may influence the maturation of the foetal brain. Clinical and preclinical findings suggest long-term consequences of SSRI perinatal exposure for the offspring. The mechanisms of SSRI effects on developing brain remain largely unknown and there are no directional approaches for prevention of the consequences of maternal SSRI treatment during pregnancy. The heptapeptide Semax (MEHFPGP) is a synthetic analogue of ACTH(4–10) which exerts marked nootropic and neuroprotective activities. The aim of the present study was to investigate the long-term effects of neonatal exposure to the SSRI fluvoxamine (FA) in white rats. Additionally, the study examined the potential for Semax to prevent the negative consequences of neonatal FA exposure. Rat pups received FA or vehicle injections on postnatal days 1–14, a time period equivalent to 27–40 weeks of human foetal age. After FA treatment, rats were administered with Semax or vehicle on postnatal days 15–28. During the 2nd month of life, the rats underwent behavioural testing, and monoamine levels in brain structures were measured. It was shown that neonatal FA exposure leads to the impaired emotional response to stress and novelty and delayed acquisition of food-motivated maze task in adolescent and young adult rats. Furthermore, FA exposure induced alterations in the monoamine levels in brains of 1- and 2- month-old rats. Semax administration reduced the anxiety-like behaviour, improved learning abilities and normalized the levels of brain biogenic amines impaired by the FA exposure. The results demonstrate that early-life FA exposure in rat pups produces long-term disturbances in their anxiety-related behaviour, learning abilities, and brain monoamines content. Semax exerts a favourable effect on behaviour and biogenic amine system of rats exposed to the antidepressant. Thus, peptide Semax can prevent behavioural deficits caused by altered 5-HT levels during development. [ABSTRACT FROM AUTHOR]

D-π-A chromophores based on novel macroacceptors − fused azinylmethylenemalononitriles (fused azine = pyrido [2,3-b]pyrazine, quinoline, quinoxaline and quinoxalin-2-one) − have been synthesized and their linear and nonlinear optical properties in gas, solution and in poled PMMA-based films have been investigated by DFT, UV–vis and second harmonic generation technique. The transition from chromophores with an azine acceptor to ones with azinylmethylenemalononitrile acceptors leads to a 10-fold increase in calculated μβ values. Poled polymer films doped with studied chromophores at 25 wt% load exhibit quadratic nonlinear optical activity with d 33 values up to 42 pm/V. [Display omitted] • Novel acceptors for NLO chromophores - fused azinylmethylenemalononitriles - are proposed. • Various push-pull azinylmethylenemalononitrile-based chromophores have been synthesized. • Macroacceptors provide tenfold increase of calculated μβ compared to azine ones. • Poled polymer films with 25 wt% chromophore load demonstrate d 33 values up to 42 p.m./V. [ABSTRACT FROM AUTHOR]

Visible particles are a critical quality attribute for parenteral products and must be monitored. A carefully designed, executed, and controlled drug product manufacturing process including a final 100 % visual inspection and appropriate end-product controls ensures that visible particles are consistently minimized and demonstrates that the injectable DP is practically free from visible particles. Visual inspection, albeit appearing as a simple analytical procedure, requires several technical and operational controls to ensure adequate performance. To gather new data on particle visibility and shed light on this decade-old challenge, a multi-company blinded visual inspection threshold study was conducted. A major goal of the study was visual assessment of several particle types of different sizes in small volume vials, as a challenging configuration for visual inspection, across 9 biopharmaceutical companies in order to determine the visibility limit. The study results provide key insights into limitations and challenges of visual inspection, namely, no universal visibility limit can be applied to all particle types as the detectability varies with particle type, number, and size. The study findings underscore the necessity of setting realistic expectations on size-based visibility limits in visual inspection, robust procedures for analyst training and qualification, and harmonization of guidelines globally. [ABSTRACT FROM AUTHOR]

Four chromophores belonging to a new class of push-pull chromophores with divinylphenylquinoxaline moieties have been designed and synthesized. The structure-property relationship was systematically investigated; the effect of the conformation on the value of chromophores first hyperpolarizability is found to be inessential. Quinoxaline-based chromophore with TCF acceptor and 7-dimethylanilinovinyl moiety displays the combination of favorable characteristics: the high value of the first hyperpolarizability, the small HOMO-LUMO energy gap, the blue shift of the absorption maximum relative to the chromophores with other divinylhetaryl or polyene π-bridges and ultrahigh thermal stability. This chromophore may be considered as a perfect candidate for the development of effective electro-optic materials. [ABSTRACT FROM AUTHOR]

Two novel chromophores with dibutylaniline donor moiety, 3,7-(di)vinylquinoxalinone π-electron bridge and tricyanofuranyl or dicyanovinyl acceptor moieties are synthesized and their properties were systematically investigated. Atomistic modeling of PMMA-based composites with the developed chromophores as guests is performed and nonlinear optical activity is studied for the first time. Atomistic modeling performed in the amorphous cell has shown that chromophore content 20 wt% may be considered most favorable for achievement of optimal d 33 values for 7-DBA-VQ on V-TCF/PMMA material. Various non-covalent interactions both between chromophores and polymer matrix and chromophores inter se were revealed in the course of modeling; these interactions could contribute to the relaxation stability of orientational order and thus quadratic NLO response. Composite material 7-DBA-VQ on V-TCF/PMMA is characterized by nonlinear-optical coefficient, d 33 , values of 97, 111 and 47 pm/V at chromophore content of 10, 20 and 30 wt%, respectively. Thus chromophore content 20 wt% provides maximal value of NLO coefficient, what is in agreement with the obtained theoretical data. The d 33 value for 7-DBA-VQ on V-DCV/PMMA is 2.5 times smaller than that for 7-DBA-VQ on V-TCF/PMMA at the same chromophore load (20 wt%). [ABSTRACT FROM AUTHOR]