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Establishing a scalable perfusion strategy for the manufacture of CAR ‐T cells in stirred‐tank bioreactors using a quality‐by‐design approach
No full textChimeric antigen receptor T cell (CAR‐T) therapies show high remission rates for relapsed and refractory leukemia and lymphoma. However, manufacturing challenges hinder their commercial viability and patient accessibility. This study applied quality‐by‐design principles to identify perfusion critical process parameters for CAR‐T expansion in stirred tank bioreactors to maximize yields. A design of experiments in the Ambr® 250 High Throughput Perfusion small‐scale bioreactor revealed that earlier perfusion starts (48 h vs. 96 h post‐inoculation) and higher perfusion rates (1.0 VVD vs. 0.25 VVD) significantly increased cytotoxic CAR‐T cell yields without compromising critical quality attributes. Optimizing perfusion improved growth kinetics and yields across donor samples, achieving densities >21 × 10 6 cells/mL in 7 days, outperforming traditional fed‐batch and static flask cultures. This study underscores the importance of optimizing perfusion parameters to maximize CAR‐T yields and quality and highlights the utility of scale‐down models in reducing time, costs and risks associated with process development.Engineering and Physical Sciences Research Council https://doi.org/10.13039/50110000026
Locally energy-stable finite element schemes for incompressible flow problems: Design and analysis for equal-order interpolations
No full texthttp://dx.doi.org/10.13039/501100001659 Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100016378 Technische Universität Dortmundhttp://dx.doi.org/10.13039/501100005416 Norges Forskningsrå
Non‐genetic factors associated with ACE‐inhibitor and angiotensin receptor blocker‐induced angioedema
No full textAbstract Background Angioedema (AE) rarely occurs as a potentially life‐threatening adverse drug reaction (ADR) to angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). The aim of the present study was to investigate non‐genetic association factors with ACEi‐/ARB‐induced angioedema in the European ADR database EudraVigilance and the database of the vARIANCE study. Methods The cohort of the vARIANCE study comprised 114 patients who suffered from ACEi‐ or ARB‐induced angioedema. In addition, 171 angioedema reports and 4650 reports on other ADRs of ACEi/ARB were identified in the ADR database EudraVigilance with the latter serving as a reference group. Odds ratios were calculated and a logistic regression analysis was performed using angioedema versus reference reports. Results Increased age, smoking, allergies and a history of previous angioedema were identified as associated factors for ACEi‐/ARB‐induced angioedema. In most patients, the swelling affected the face, lips and tongue. In the vARIANCE study, about 70% of angioedema occurred after 1 year of treatment. For one in two patients in the vARIANCE study (84.2% with ACEi treatment) and one in three patients from the EudraVigilance reports (59.6% with ARB treatment), the angioedema resulted in hospitalization. Conclusions We found small to moderate associations with certain individual patient‐related factors in this pharmaco‐epidemiological study. As a future perspective, combining non‐genetic association factors with corresponding genetic data might provide an option to compose stronger and individual risk scores
Quality of life after two sequences of total neoadjuvant treatment in patients with locally advanced rectal cancer in the randomized CAO/ARO/AIO-12 phase 2 trial
No full text501100005972 German Cancer Ai
Radio(chemo)therapy with curative intent for anal cancer - effectiveness and toxicity in elderly vs. younger patients
No full textPrimary radio(chemo)therapy is a therapeutic standard strategy for advanced anal squamous cell carcinoma (ASCC). For elderly patients evidence concerning long-term oncological outcome is scarce.Open-Access-Publikationsfonds 202
Females prioritize future over current offspring in wild seasonally breeding Assamese macaques
No full textClassical work on birds by David Lack was foundational to life history theory when it uncovered a trade-off between offspring quantity and quality. Evidence for a similar trade-off was later found in singleton-bearing mammals, but its extent and underlying mechanisms are not fully understood. Here, we explore the role of adaptive reproductive scheduling and maternal energy depletion as the basis of the trade-off with data on 410 births by 104 mothers recorded over 18 years in a wild Assamese macaque (Macaca assamensis) population with seasonal reproduction. In any given mating season and after controlling for maternal age effects, the probability for a female to conceive was strongly predicted by the presence of a dependent offspring. The younger the current infant was, the less likely mothers were to invest in a new reproductive event, possibly to avoid stacked investment into nursing and unborn offspring. An inverse relationship between current infant survival and the conception of a new sibling points toward a shift in maternal resource allocation to future offspring. However, to avoid the energetic drain of shorter birth intervals, mothers delayed their reproductive timing within the mating season by 49 days with negative downstream effects for the next reproductive opportunity
Evaluating a brief imagery-based intervention for adolescent depression: study protocol for a Phase IIB randomised control trial (INDIGO) in secondary schools
No full textAbstract Background There is an urgent need for psychological interventions that can target depression in late adolescence and prevent it from having lifelong implications. Schools have been identified as a promising setting to enhance access to interventions and offer support earlier. We have co-developed a novel intervention, IMAGINE, that targets key cognitive mechanisms implicated in depression across the lifespan. Depression has been associated with distressing negative mental images, a deficit in positive future images and overgeneral autobiographical memories. Interventions targeting these factors have shown clinical promise in adults. Here, we combine techniques targeting these cognitive processes into a novel, brief psychological intervention for adolescent depression. This Phase IIb randomised controlled trial will evaluate IMAGINE compared to an active psychological intervention. Methods/design One hundred sixty adolescents (aged 16–18) with high levels of depressive symptoms will be recruited from schools. Participants will be randomly allocated to IMAGINE or the active psychological control intervention, non-directive support (NDS). Assessment will take place at baseline, 8-, 16- and 24-week post randomisation. The primary objective is to establish whether IMAGINE reduces symptoms of depression, relative to NDS, at 8 weeks following randomisation. Secondary objectives include whether changes in depression are maintained at 16- and 24-week follow-up, the efficacy of IMAGINE on secondary clinical outcomes and key cognitive mechanisms and, finally, to assess outcomes around acceptability, safety and adherence. Discussion If IMAGINE is shown to be safe and clinically effective, an effectiveness-implementation hybrid RCT will be indicated. If rolled out as an intervention, IMAGINE would significantly extend the range of effective therapies available for adolescent depression. Trial registration ISRCTN, ISRCTN14015295. Registered 11 September 2023, https://doi.org/10.1186/ISRCTN14015295
