Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: Off-the-shelf GMP-manufactured donor-independent ATMP

© 2020, The Author(s). Background: Human dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an easily accessible MSC population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated not only with skin-related but also systemic inflammatory and/or degenerative processes. Methods: We have developed a validated Good Manufacturing Practice-compliant expansion and manufacturing process by which ABCB5+ MSCs derived from surgical discard skin tissues are processed to an advanced-therapy medicinal product (ATMP) for clinical use. Enrichment for ABCB5+ MSCs is achieved in a three-step process involving plastic adherence selection, expansion in a highly efficient MSC-selecting medium, and immunomagnetic isolation of the ABCB5+ cells from the mixed culture. Results: Product Quality Review data covering 324 cell expansions, 728 ABCB5+ MSC isolations, 66 ABCB5+ MSC batches, and 85 final drug products reveal high process robustness and reproducible, reliable quality of the manufactured cell therapy product. Conclusion: We have successfully established an expansion and manufacturing process that enables the generation of homogenous ABCB5+ MSC populations of proven biological activity manufactured as a standardized, donor-independent, highly pure, and highly functional off-the-shelf available ATMP, which is currently tested in multiple clinical trials

Effectiveness, cost-effectiveness and cost-benefit of a single annual professional intervention for the prevention of childhood dental caries in a remote rural Indigenous community

Background The aim of the study is to reduce the high prevalence of tooth decay in children in a remote, rural Indigenous community in Australia, by application of a single annual dental preventive intervention. The study seeks to (1) assess the effectiveness of an annual oral health preventive intervention in slowing the incidence of dental caries in children in this community, (2) identify the mediating role of known risk factors for dental caries and (3) assess the cost-effectiveness and cost-benefit of the intervention. Methods/design The intervention is novel in that most dental preventive interventions require regular re-application, which is not possible in resource constrained communities. While tooth decay is preventable, self-care and healthy habits are lacking in these communities, placing more emphasis on health services to deliver an effective dental preventive intervention. Importantly, the study will assess cost-benefit and cost-effectiveness for broader implementation across similar communities in Australia and internationally. Discussion There is an urgent need to reduce the burden of dental decay in these communities, by implementing effective, cost-effective, feasible and sustainable dental prevention programs. Expected outcomes of this study include improved oral and general health of children within the community; an understanding of the costs associated with the intervention provided, and its comparison with the costs of allowing new lesions to develop, with associated treatment costs. Findings should be generalisable to similar communities around the world. The research is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registration number ACTRN12615000693527; date of registration: 3rd July 2015

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bio-Inspired Magnetically Controlled Reversibly Actuating Multimaterial Fibers

Movements in plants, such as the coiling of tendrils in climbing plants, have been studied as inspiration for coiling actuators in robotics. A promising approach to mimic this behavior is the use of multimaterial systems that show different elastic moduli. Here, we report on the development of magnetically controllable/triggerable multimaterial fibers (MMFs) as artificial tendrils, which can reversibly coil and uncoil on stimulation from an alternating magnetic field. These MMFs are based on deformed shape-memory fibers with poly[ethylene-co-(vinyl acetate)] (PEVA) as their core and a silicone-based soft elastomeric magnetic nanocomposite shell. The core fiber provides a temperature-dependent expansion/contraction that propagates the coiling of the MMF, while the shell enables inductive heating to actuate the movements in these MMFs. Composites with mNP weight content ≥ 15 wt% were required to achieve heating suitable to initiate movement. The MMFs coil upon application of the magnetic field, in which a degree of coiling N = 0.8 ± 0.2 was achieved. Cooling upon switching OFF the magnetic field reversed some of the coiling, giving a reversible change in coiling ∆n = 2 ± 0.5. These MMFs allow magnetically controlled remote and reversible actuation in artificial (soft) plant-like tendrils, and are envisioned as fiber actuators in future robotics applications

Two Different Heated Tobacco Products vs. Cigarettes: Comparison of Nicotine Delivery and Subjective Effects in Experienced Users

Heated tobacco products (HTPs) produce aerosol using a different mechanism than tobacco cigarettes, leading to lower emissions of some harmful substances, but also of nicotine as reported by some independent studies. Lower nicotine delivery could lead to compensatory puffing when product use does not sufficiently satisfy cravings. Thus, this three-arm crossover study was conducted to characterize the potential of two different HTPs to deliver nicotine and satisfy cravings compared with conventional cigarettes in users who had already switched to HTPs. Fifteen active, non-exclusive HTP users consumed the study products according to a pre-directed puffing protocol. At predetermined time points, venous blood was sampled and the subjective effects of consumption were assessed. Nicotine delivery by both HTPs was comparable, but significantly lower than that by conventional cigarettes, suggesting a lower addictive potential. Cravings were reduced by all products, with no statistically significant differences between them, despite the different nicotine deliveries. This indicated that HTPs do not necessarily need high nicotine deliveries with high addictive potential, as are characteristic of tobacco cigarettes. These results were followed up on with an ad libitum use study

Guidelines for the use of flow cytometry and cell sorting in immunological studies

International audienceThe classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127(-) and CD127(+) early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127(-) and CD127(+) ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127(-) ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127(+) ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a "two-family" model of human lymphoid development that differs from the prevailing model of hematopoiesis