Overcoming manufacturing challenges for an early phase development program

Speed to clinic often does not allow for in-depth manufacturing process development and understanding of early phase clinical programs; however, this may be necessary when inconsistencies in process performance or product quality are observed. For a recent Phase 1 fed-batch process, drug substance manufacturing process variability was observed during development and manufacturing scale productions. Process performance variability was observed during upstream process with ending viability ranging from 90% to 60% and end product neutral glycan profile ranging from 15% to 50%. To mitigate future performance variability, two approaches were taken: 1) improve cell culture performance robustness and 2) probe the relationship between cell culture performance and product quality attributes. Using ambr®15 as a high-throughput screening tool, a series of risk-based process parameter screening studies were conducted to eliminate potential root causes for culture viability decline. Small scale studies, both at ambr®15 and benchtop bioreactor scales, offered insights suggesting shear sensitivity and raw material variability were potential contributors to inconsistent cell culture performance. Strategic process-specific alterations, such as changing aeration method and lowering the agitation intensity, resulted in culture health improvements. Small scale results also indicated high-risk medium lots may be identified and mitigated with additional shear protectants. Large scale manufacturing in-process data suggest glycosylation pattern may not be directly linked to cell culture viability. Further studies may be useful to identify other process steps that contribute to product quality variations. Learnings from this presentation highlight strategies to improve cell culture performance robustness and the need to establish the relationship between in-process attributes and end product quality

On the causes of economic growth in Europe: why did agricultural labour productivity not converge between 1950 and 2005?

The objective of this study is to make a further contribution to the debate on the causes of economic growth in the European Continent. It explains why agricultural labour productivity differences did not converge between 1950 and 2005 in Europe. We propose an econometric model, one combining both proximate and fundamental causes of economic growth. The results show that the continuous exit of labour power from the sector, coupled with the increased use of productive factors originating in other sectors of the economy, caused the efficiency of agricultural workers to rise. However, we offer a complete explanation of the role played by institutions and geographical factors. Thus, we detect a direct and inverse relation between membership of the EU and the Communist bloc and the productivity of agricultural labour. In addition, strong support for agriculture affected productivity negatively

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions

Hydrogel rectum-prostate spacers mitigate the uncertainties in proton relative biological effectiveness associated with anterior-oblique beams

<p><b>Aim:</b> Anterior-oblique (AO) proton beams can form an attractive option for prostate patients receiving external beam radiotherapy (EBRT) as they avoid the femoral heads. For a cohort with hydrogel prostate-rectum spacers, we asked whether it was possible to generate AO proton plans robust to end-of-range elevations in linear energy transfer (LET) and modeled relative biological effectiveness (RBE). Additionally we considered how rectal spacers influenced planned dose distributions for AO and standard bilateral (SB) proton beams versus intensity-modulated radiotherapy (IMRT).</p> <p><b>Material and methods:</b> We studied three treatment strategies for 10 patients with rectal spacers: (A) AO proton beams, (B) SB proton beams and (C) IMRT. For strategy (A) dose and LET distributions were simulated (using the TOPAS Monte Carlo platform) and the McNamara model was used to calculate proton RBE as a function of LET, dose per fraction, and photon α/β. All calculations were performed on pretreatment scans: inter- and intra-fractional changes in anatomy/set-up were not considered.</p> <p><b>Results:</b> For 9/10 patients, rectal spacers enabled generation of AO proton plans robust to modeled RBE elevations: rectal dose constraints were fulfilled even when the variable RBE model was applied with a conservative α/β = 2 Gy. Amongst a subset of patients the proton rectal doses for the planning target volume plans were remarkably low: for 2/10 SB plans and 4/10 AO plans, ≤10% of the rectum received ≥20 Gy. AO proton plans delivered integral doses a factor of approximately three lower than IMRT and spared the femoral heads almost entirely.</p> <p><b>Conclusion:</b> Typically, rectal spacers enabled the generation of anterior beam proton plans that appeared robust to modeled variation in RBE. However, further analysis of day-to-day robustness would be required prior to a clinical implementation of AO proton beams. Such beams offer almost complete femoral head sparing, but their broader value relative to IMRT and SB protons remains unclear.</p