Concise Review: Mind the Gap: Challenges in Characterizing and Quantifying Cell- and Tissue-Based Therapies for Clinical Translation

There are many challenges associated with characterizing and quantifying cells for use in cell- and tissue-based therapies. From a regulatory perspective, these advanced treatments must not only be safe and effective but also be made by high-quality manufacturing processes that allow for on-time delivery of viable products. Although sterility assays can be adapted from conventional bioprocessing, cell- and tissue-based therapies require more stringent safety assessments, especially in relation to use of animal products, immune reaction, and potential instability due to extended culture times. Furthermore, cell manufacturers who plan to use human embryonic stem cells in their therapies need to be particularly stringent in their final purification steps, due to the unrestricted growth potential of these cells. This review summarizes the current issues in characterization and quantification for cell- and tissue-based therapies, dividing these challenges into the regulatory themes of safety, potency, and manufacturing quality. It outlines current assays in use, as well as highlights the limits of many of these product release tests. Mode of action is discussed, with particular reference to in vitro surrogate assays that can be used to provide information to correlate with proposed in vivo patient efficacy. Importantly, this review highlights the requirement for basic research to improve current knowledge on the in vivo fate of these treatments; as well as an improved stakeholder negotiation process to identify the measurement requirements that will ensure the manufacture of the best possible cell- and tissue-based therapies within the shortest timeframe for the most patient benefit

A Research and Practice Brief: Measuring Compliance with the Indian Child Welfare Act

This research and practice brief by Casey Family Programs is a useful resource for states that seek to document compliance with ICWA. We document different approaches for measuring compliance and make some recommendations including increased resources to support and to develop training mechanisms for child protective services and judicial staff. Standard measures for compliance across jurisdictions would be beneficial

Regenerative medicine, resource and regulation: lessons learned from the remedi project

The successful commercialization of regenerative medicine products provides a unique challenge to the manufacturer owing to a lack of suitable investment/business models and a constantly evolving regulatory framework. The resultant slow translation of scientific discovery into safe and clinically efficacious therapies is preventing many potential products from reaching the market. This is despite of the need for new therapies that may reduce the burden on the world’s healthcare systems and address the desperate need for replacement tissues and organs. The collaborative Engineering and Physical Sciences Research Council (EPSRC)-funded remedi project was devised to take a holistic but manufacturing-led approach to the challenge of translational regenerative medicine in the UK. Through strategic collaborations and discussions with industry and other academic partners, many of the positive and negative issues surrounding business and regulatory success have been documented to provide a remedi-led perspective on the management of risk in business and the elucidation of the regulatory pathways, and how the two are inherently linked. This article represents the findings from these discussions with key stakeholders and the research into best business and regulatory practices

Neuroprotective efficacy of P7C3 compounds in primate hippocampus.

There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2-11, monkeys received weekly injection of 5'-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well

Role of PKR and Type I IFNs in Viral Control during Primary and Secondary Infection

Type I interferons (IFNs) are known to mediate viral control, and also promote survival and expansion of virus-specific CD8+ T cells. However, it is unclear whether signaling cascades involved in eliciting these diverse cellular effects are also distinct. One of the best-characterized anti-viral signaling mechanisms of Type I IFNs is mediated by the IFN-inducible dsRNA activated protein kinase, PKR. Here, we have investigated the role of PKR and Type I IFNs in regulating viral clearance and CD8+ T cell response during primary and secondary viral infections. Our studies demonstrate differential requirement for PKR, in viral control versus elicitation of CD8+ T cell responses during primary infection of mice with lymphocytic choriomeningitis virus (LCMV). PKR-deficient mice mounted potent CD8+ T cell responses, but failed to effectively control LCMV. The compromised LCMV control in the absence of PKR was multifactorial, and linked to less effective CD8+ T cell-mediated viral suppression, enhanced viral replication in cells, and lower steady state expression levels of IFN-responsive genes. Moreover, we show that despite normal expansion of memory CD8+ T cells and differentiation into effectors during a secondary response, effective clearance of LCMV but not vaccinia virus required PKR activity in infected cells. In the absence of Type I IFN signaling, secondary effector CD8+ T cells were ineffective in controlling both LCMV and vaccinia virus replication in vivo. These findings provide insight into cellular pathways of Type I IFN actions, and highlight the under-appreciated importance of innate immune mechanisms of viral control during secondary infections, despite the accelerated responses of memory CD8+ T cells. Additionally, the results presented here have furthered our understanding of the immune correlates of anti-viral protective immunity, which have implications in the rational design of vaccines

Normative Data for the NeuroCom Sensory Organization Test in US Military Special Operations Forces.

CONTEXT: Postural stability is the ability to control the center of mass in relation to a person\u27s base of support and can be affected by both musculoskeletal injury and traumatic brain injury. The NeuroCom Sensory Organization Test (SOT) can be used to objectively quantify impairments to postural stability. The ability of postural stability to predict injury and be used as an acute injury-evaluation tool makes it essential to the screening and rehabilitation process. To our knowledge, no published normative data for the SOT from a healthy, highly active population are available for use as a reference for clinical decision making. OBJECTIVE: To present a normative database of SOT scores from a US Military Special Operations population that can be used for future comparison. DESIGN: Cross-sectional study. SETTING: Human performance research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 542 active military operators from Naval Special Warfare Combatant-Craft Crewmen (n = 149), Naval Special Warfare Command, Sea, Air, and Land (n = 101), US Army Special Operations Command (n = 171), and Air Force Special Operations Command (n = 121). MAIN OUTCOME MEASURE(S): Participants performed each of the 6 SOT conditions 3 times. Scores for each condition, total equilibrium composite score, and ratio scores for the somatosensory, visual, and vestibular systems were recorded. RESULTS: Differences were present across all groups for SOT conditions 1 (P \u3c .001), 2 (P = .001), 4 (P \u3e .001), 5 (P \u3e .001), and 6 (P = .001) and total equilibrium composite (P = .000), visual (P \u3e .001), vestibular (P = .002), and preference (P \u3e .001) NeuroCom scores. CONCLUSIONS: Statistical differences were evident in the distribution of postural stability across US Special Operations Forces personnel. This normative database for postural stability, as assessed by the NeuroCom SOT, can provide context when clinicians assess a Special Operations Forces population or any other groups that maintain a high level of conditioning and training

Stable Scheduling Increases Productivity and Sales

Variable schedules are now the norm for part-time workers in a variety of industries including retail, where schedules typically change every day and every week, with three to seven days' notice of the next week's schedule. In recent years, these scheduling practices have come under increasing scrutiny in state attorney general offices, state and local legislatures, and the media. In retail, unstable schedules for employees have been considered an inevitable outcome of stores' need for profitability. Operations researchers have found that matching labor to incoming traffic is a key driver of retail store profitability (Perdikaki et al., 2012). At the same time, social scientists have studied the deleterious effects of variable schedules on employee wellbeing (Henly & Lambert, 2014). What has been lacking is evidence that schedules in service-sector jobs can be improved in ways that benefit both employers and employees

Qualification of academic facilities for small-scale automated manufacture of autologous cell-based products

Academic centres, hospitals and small companies, as typical development settings for UK regenerative medicine assets, are significant contributors to the development of autologous cell-based therapies. Often lacking the appropriate funding, quality assurance heritage or specialist regulatory expertise, qualifying aseptic cell processing facilities for Good Manufacturing Practice (GMP) compliance is a significant challenge. The qualification of a new Cell Therapy Manufacturing Facility (CTMF) with automated processing capability, the first of its kind in a UK academic setting, provides a unique demonstrator for the qualification of small-scale, automated facilities for GMP compliant manufacture of autologous cell-based products in these settings. This paper shares our experiences in qualifying the CTMF, focussing on our approach to streamlining the qualification effort, the challenges, project delays and inefficiencies we encountered and the subsequent lessons learned

Factors associated with overweight cats successfully completing a diet-based weight loss programme: an observational study

Background The most common approach for controlled weight loss in cats is dietary caloric restriction, using a purpose-formulated diet. Most previous studies have only assessed short-term outcomes, and no previous study has examined overall success (i.e. odds of reaching target weight). The aim of this study was to determine the factors associated with overweight cats successfully completing a diet-based weight loss programme to reach target weight. Results Sixty-two cats were included, and 28 (45%) completed their weight loss programme. The remaining 34 cats (55%) did not reach target weight, of which 2 (3%) were euthanised for unrelated reasons. Reasons for cats stopping the programme prematurely included inability to contact owner (n = 19), owner requested that the programme be completed prior to reaching target weight (n = 5), the cat developed another illness (n = 3), refusal to comply with requirements for weight management (n = 2), owner illness (n = 2), and personal issues of the owner (n = 1). Multiple logistic regression analysis revealed that rate of weight loss and weight loss required were positively (odds ratio [OR] 157.81, 95% confidence interval [CI] 10.00–2492.67) and negatively (OR 0.89, 95% CI 0.81–0.98) associated with the odds of completing the weight loss programme, respectively. Conclusions Future studies should consider developing better methods of supporting the owners of the most obese cats during weight management, since these cats are least likely to complete reach target weight