bluuebunny/crossref_metadata_2025 huggingface dataset:
Map-based cosmology inference with lognormal cosmic shear maps
Authors: Boruah Supranta S , Rozo Eduardo , Fiedorowicz Pier
Published: September 2022

Most cosmic shear analyses to date have relied on summary statistics (e.g. ξ+ and ξ−). These types of analyses are necessarily suboptimal, as the use of summary statistics is lossy. In this paper, we forward-model the convergence field of the Universe as a lognormal random field conditioned on the observed shear data. This new map-based inference framework enables us to recover the joint posterior of the cosmological parameters and the convergence field of the Universe. Our analysis properly accounts for the covariance in the mass maps across tomographic bins, which significantly improves the fidelity of the maps relative to single-bin reconstructions. We verify that applying our inference pipeline to Gaussian random fields recovers posteriors that are in excellent agreement with their analytical counterparts. At the resolution of our maps – and to the extent that the convergence field can be described by the lognormal model – our map posteriors allow us to reconstruct all summary statistics (including non-Gaussian statistics). We forecast that a map-based inference analysis of LSST-Y10 data can improve cosmological constraints in the σ8–Ωm plane by $\approx\!{30}{{\ \rm per\ cent}}$ relative to the currently standard cosmic shear analysis. This improvement happens almost entirely along the $S_8=\sigma _8\Omega _{\rm m}^{1/2}$ directions, meaning map-based inference fails to significantly improve constraints on S8.
GROWTH on S190426c II: GROWTH-India Telescope search for an optical counterpart with a custom image reduction and candidate vetting pipeline
Authors: Kumar Harsh , Bhalerao Varun , Anupama G C , Barway Sudhanshu , Coughlin Michael W , De Kishalay , Deshmukh Kunal , Dutta Anirban , Goldstein Daniel A , Jassani Adeem , Joharle Simran , Karambelker Viraj , Khandagale Maitreya , Kumar Brajesh , Saraogi Divita , Sharma Yashvi , Shenoy Vedant , singer Leo , Singh Avinash , Waratkar Gaurav
Published: September 2022

S190426c/GW190426_152155 was the first probable neutron star–black hole merger candidate detected by the LIGO-Virgo Collaboration. We undertook a tiled search for optical counterparts of this event using the 0.7-m GROWTH-India Telescope. Over a period of two weeks, we obtained multiple observations over a 22.1 deg2 area, with a 17.5 per cent probability of containing the source location. Initial efforts included obtaining photometry of sources reported by various groups, and a visual search for sources in all galaxies contained in the region. Subsequently, we have developed an image subtraction and candidate vetting pipeline with $\sim 94{{\ \rm per\ cent}}$ efficiency for transient detection. Processing the data with this pipeline, we find several transients, but none that are compatible with kilonova models. We present the details of our observations, the working of our pipeline, results from the search, and our interpretations of the non-detections that will work as a pathfinder during the O4 run of LVK.
A measurement of Hubble’s Constant using Fast Radio Bursts
Authors: James C W , Ghosh E M , Prochaska J X , Bannister K W , Bhandari S , Day C K , Deller A T , Glowacki M , Gordon A C , Heintz K E , Marnoch L , Ryder S D , Scott D R , Shannon R M , Tejos N
Published: September 2022

We constrain the Hubble constant H0 using Fast Radio Burst (FRB) observations from the Australian Square Kilometre Array Pathfinder (ASKAP) and Murriyang (Parkes) radio telescopes. We use the redshift-dispersion measure (‘Macquart’) relationship, accounting for the intrinsic luminosity function, cosmological gas distribution, population evolution, host galaxy contributions to the dispersion measure (DMhost), and observational biases due to burst duration and telescope beamshape. Using an updated sample of 16 ASKAP FRBs detected by the Commensal Real-time ASKAP Fast Transients (CRAFT) Survey and localized to their host galaxies, and 60 unlocalized FRBs from Parkes and ASKAP, our best-fitting value of H0 is calculated to be $73_{-8}^{+12}$ km s−1 Mpc−1. Uncertainties in FRB energetics and DMhost produce larger uncertainties in the inferred value of H0 compared to previous FRB-based estimates. Using a prior on H0 covering the 67–74 km s−1 Mpc−1 range, we estimate a median ${\rm DM}_{\rm host}= 186_{-48}^{+59}\,{\rm pc \, cm^{-3}}$, exceeding previous estimates. We confirm that the FRB population evolves with redshift similarly to the star-formation rate. We use a Schechter luminosity function to constrain the maximum FRB energy to be log10Emax$=41.26_{-0.22}^{+0.27}$ erg assuming a characteristic FRB emission bandwidth of 1 GHz at 1.3 GHz, and the cumulative luminosity index to be $\gamma =-0.95_{-0.15}^{+0.18}$. We demonstrate with a sample of 100 mock FRBs that H0 can be measured with an uncertainty of ±2.5 km s−1 Mpc−1, demonstrating the potential for clarifying the Hubble tension with an upgraded ASKAP FRB search system. Last, we explore a range of sample and selection biases that affect FRB analyses.
Asymptotic model for a bi-component system with a very large mass ratio mh/ml of their constituting particles
Authors: Gomez-Leyton Yuvineza J , Velazquez Luisberis
Published: September 2022

We address the asymptotic limit of the γ-exponential model for a bi-component system with a very large ratio mh/ml between the masses of their constituting particles. The simplest model that captures this limit situation is an isothermal gas of non-relativistic point particles under an external harmonic potential $V\left(\mathbf {r}\right)=m\, \omega ^{2}_{0}\, \mathbf {r}^{2}/2$ that mimics the gravitational influence of the lightest particles in the central regions. We revisit the study of this self-gravitating model by including the anisotropy due to the system rotation. The thermodynamics of this situation is hallmarked by the gravitational radius$r_{c}=\left(G\, M/\omega ^{2}_{0}\right)^{1/3}$ and finite values of the rotation frequency ω < ω0, where M is the system total mass. The axially symmetric solutions of this model predicts spheroidal profiles with any value of the angular momentum, whose anisotropy is driven via the dimensionless parameter $\varepsilon =\omega ^{2}/\omega ^{2}_{0}$. In general, the thermodynamics is significantly affected by the system rotation. Considering the limit ε → 1, in particular, our calculations predict that the temperature at gravothermal collapse goes to zero and the main components of the inertia tensor diverge. Finally, we apply the present model to perform an analysis of star distributions under the gravitational influence of dark matter haloes in some dwarf spheroidal galaxies. Our interest is focused on the applicability conditions of the present model to these stellar systems.
Algebraic and machine learning approach to hierarchical triple-star stability
Authors: Vynatheya Pavan , Hamers Adrian S , Mardling Rosemary A , Bellinger Earl P
Published: September 2022

We present two approaches to determine the dynamical stability of a hierarchical triple-star system. The first is an improvement on the Mardling–Aarseth stability formula from 2001, where we introduce a dependence on inner orbital eccentricity and improve the dependence on mutual orbital inclination. The second involves a machine learning approach, where we use a multilayer perceptron (MLP) to classify triple-star systems as ‘stable’ and ‘unstable’. To achieve this, we generate a large training data set of 106 hierarchical triples using the N-body code MSTAR. Both our approaches perform better than previous stability criteria, with the MLP model performing the best. The improved stability formula and the machine learning model have overall classification accuracies of $93{{\ \rm per\ cent}}$ and $95{{\ \rm per\ cent}}$ respectively. Our MLP model, which accurately predicts the stability of any hierarchical triple-star system within the parameter ranges studied with almost no computation required, is publicly available on Github in the form of an easy-to-use python script.
Characterising murine hippocampal iron homeostasis, in relation to markers of brain inflammation and metabolism, during ageing
Authors: Ellison Gaewyn , Duong Lelinh , Hollings Ashley , Howard Daryl , Jackaman Connie , Hackett Mark J
Published: September 2022

Metal ions (Fe, Cu, and Zn) are essential to a healthy brain function, with the amount, localisation, and chemical form often tightly controlled. Evidence points towards loss of metal ion homeostasis within the ageing brain; in particular brain Fe accumulation appears to be a hallmark of ageing, which may place the brain at a greater risk of neurodegenerative disease. Unfortunately, the cause or consequence of altered brain metal ion homeostasis during ageing remains unknown, and there is a lack of data comparing brain metal ion homeostasis with other events of the ageing process (e.g. brain metabolism, brain inflammation). This study has utilised a multi-modal approach that incorporated: X-ray fluorescence microscopy for elemental mapping of metal ion homeostasis, Perl's Fe histochemistry, FTIR spectroscopic biochemical imaging of lactate and protein aggregates, and immuno-fluorescence analysis of markers of brain inflammation and Fe storage proteins (heavy-chain ferritin, light-chain ferritin, and mitochondrial ferritin). Interestingly, while age-related Fe accumulation was observed in corpus callosum white matter of murine (C56BL/6J) brain tissue (concomitant with elevated levels of markers of brain inflammation and altered metabolism), Fe content was not altered within the hippocampus (a decrease in total Zn within the mossy fibres was observed). Ultimately, the results of this study demonstrate an important association between elevated brain Fe and brain inflammation during natural ageing. This study also highlights that future research is required to image different chemical forms of Fe with respect to changes in brain metabolism and inflammation, as well as localising these changes to specific cell types.
The absence of the queuosine tRNA modification leads to pleiotropic phenotypes revealing perturbations of metal and oxidative stress homeostasis in Escherichia coli K12
Authors: Pollo-Oliveira Leticia , Davis Nick K , Hossain Intekhab , Ho Peiying , Yuan Yifeng , Salguero García Pedro , Pereira Cécile , Byrne Shane R , Leng Jiapeng , Sze Melody , Blaby-Haas Crysten E , Sekowska Agnieszka , Montoya Alvaro , Begley Thomas , Danchin Antoine , Aalberts Daniel P , Angerhofer Alexander , Hunt John , Conesa Ana , Dedon Peter C , de Crécy-Lagard Valérie
Published: September 2022

Queuosine (Q) is a conserved hypermodification of the wobble base of tRNA containing GUN anticodons but the physiological consequences of Q deficiency are poorly understood in bacteria. This work combines transcriptomic, proteomic and physiological studies to characterize a Q-deficient Escherichia coli K12 MG1655 mutant. The absence of Q led to an increased resistance to nickel and cobalt, and to an increased sensitivity to cadmium, compared to the wild-type (WT) strain. Transcriptomic analysis of the WT and Q-deficient strains, grown in the presence and absence of nickel, revealed that the nickel transporter genes (nikABCDE) are downregulated in the Q– mutant, even when nickel is not added. This mutant is therefore primed to resist to high nickel levels. Downstream analysis of the transcriptomic data suggested that the absence of Q triggers an atypical oxidative stress response, confirmed by the detection of slightly elevated reactive oxygen species (ROS) levels in the mutant, increased sensitivity to hydrogen peroxide and paraquat, and a subtle growth phenotype in a strain prone to accumulation of ROS.
Gallium(III)-pyridoxal thiosemicarbazone derivatives as nontoxic agents against Gram-negative bacteria
Authors: Scaccaglia Mirco , Rega Martina , Vescovi Marianna , Pinelli Silvana , Tegoni Matteo , Bacci Cristina , Pelosi Giorgio , Bisceglie Franco
Published: September 2022

Many bacterial strains are developing mechanism of resistance to antibiotics, rendering last-resort antibiotics inactive. Therefore, new drugs are needed and in particular metal-based compounds represent a valid starting point to explore new antibiotic classes. In this study, we have chosen to investigate gallium(III) complexes for their potential antimicrobial activity against different strains of Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa which have developed different type of resistance mechanism, including the expression of β-lactamases (NDM-1, ESβL, or AmpC) or the production of biofilm. We studied a series of thiosemicarbabazones derived from pyridoxal, their related Ga(III) complexes, and the speciation in solution of the Ga(III)/ligand systems as a function of the pH. Proton dissociation constants and conditional stability constants of Ga(III) complexes were evaluated by UV/Vis spectroscopy, and the most relevant species at physiological pH were identified. The compounds are active against resistant Gram-negative strain with minimal inhibitory concentration in the μM range, while no cytotoxicity was detected in eukaryotic cells.
Kidney transplantation during mass disasters—from COVID-19 to other catastrophes: a Consensus Statement by the DESCARTES Working Group and Ethics Committee of the ERA
Authors: Sever Mehmet Sukru , Vanholder Raymond , Oniscu Gabriel , Abramowicz Daniel , Van Biesen Wim , Maggiore Umberto , Watschinger Bruno , Mariat Christophe , Buturovic-Ponikvar Jadranka , Crespo Marta , Mjoen Geir , Heering Peter , Peruzzi Licia , Gandolfini Ilaria , Hellemans Rachel , Hilbrands Luuk
Published: September 2022

Mass disasters are characterized by a disparity between healthcare demand and supply, which hampers complex therapies like kidney transplantation. Considering the scarcity of publications on previous disasters, we reviewed transplantation practice during the recent coronavirus disease 2019 (COVID-19) pandemic, and dwelled upon this experience to guide transplantation strategies in the future pandemic and non-pandemic catastrophes. We strongly suggest continuing transplantation programs during mass disasters, if medical and logistic operational circumstances are appropriate. Postponing transplantations from living donors and referral of urgent cases to safe regions or hospitals are justified. Specific preventative measures in anticipated disasters (such as vaccination programs during pandemics or evacuation in case of hurricanes or wars) may be useful to minimize risks. Immunosuppressive therapies should consider stratifying risk status and avoiding heavy immune suppression in patients with a low probability of therapeutic success. Discharging patients at the earliest convenience is justified during pandemics, whereas delaying discharge is reasonable in other disasters, if infrastructural damage results in unhygienic living environments for the patients. In the outpatient setting, telemedicine is a useful approach to reduce the patient load to hospitals, to minimize the risk of nosocomial transmission in pandemics and the need for transport in destructive disasters. If it comes down to saving as many lives as possible, some ethical principles may vary in function of disaster circumstances, but elementary ethical rules are non-negotiable. Patient education is essential to minimize disaster-related complications and to allow for an efficient use of healthcare resources.
The 5ʹ-3ʹ mRNA Decay Pathway Modulates the Plant Circadian Network inArabidopsis
Authors: Careno Daniel A , Perez Santangelo Soledad , Macknight Richard C , Yanovsky Marcelo J
Published: September 2022

Circadian rhythms enable organisms to anticipate and adjust their physiology to periodic environmental changes. These rhythms are controlled by biological clocks that consist of a set of clock genes that regulate each other’s expression. Circadian oscillations in messenger RNA (mRNA) levels require the regulation of mRNA production and degradation. While transcription factors controlling clock function have been well characterized from cyanobacteria to humans, the role of factors controlling mRNA decay is largely unknown. Here, we show that mutations in SM-LIKE PROTEIN 1 (LSM1) and exoribonucleases 4 (XRN4), components of the 5ʹ-3ʹ mRNA decay pathway, alter clock function in Arabidopsis. We found that lsm1 and xrn4 mutants display long-period phenotypes for clock gene expression. In xrn4, these circadian defects were associated with changes in circadian phases of expression, but not overall mRNA levels, of several core-clock genes. We then used noninvasive transcriptome-wide mRNA stability analysis to identify genes and pathways regulated by XRN4. Among genes affected in the xrn4 mutant at the transcriptional and posttranscriptional level, we found an enrichment in genes involved in auxin, ethylene and drought recovery. Large effects were not observed for canonical core-clock genes, although the mRNAs of several auxiliary clock genes that control the pace of the clock were stabilized in xrn4 mutants. Our results establish that the 5ʹ-3ʹ mRNA decay pathway constitutes a novel posttranscriptional regulatory layer of the circadian gene network, which probably acts through a combination of small effects on mRNA stability of several auxiliary and some core-clock genes.
Abstract 1 Distinctive and Differentiation-State Dependent DNA Damage Response of Hematopoietic Stem Cells to Genotoxic Noxae
Authors: Becker Fabienne , Ouzin Meryem , Lucks Luzie , Christ Kathrin , Liedtke Stefanie , Kögler Gesine
Published: September 2022

Introduction

Hematopoietic stem cells (HSCs) sustain lifelong blood production and can be used in allogenic stem cell transplantation for treatment of hematological malignancies, yet the mechanisms of their DNA damage response (DDR) remain largely unexplored. Genotoxic damage can be induced by chemotherapeutical agents (eg, etoposide, a topoisomerase II inhibitor) or by methylating agents (eg, nitrosamines). Related double strand breaks (DSBs) at the level of immature cells are thus presumed to trigger leukemia.

Objective

Human quiescent and cycling HSCs were reported to exhibit distinct responses to genotoxic stress upon in vitro exposure to sublethal doses of etoposide or N-nitroso-N-methylurea (MNU). In this context, we aim to identify and compare the mechanisms involved in the determination of HSC stem and progenitor cell fate upon DNA damage to gain more insights into cytotoxic anticancer drug- and contaminant-related hematological toxicity.

Methods

Quiescent human HSCs (CD34+) were isolated from umbilical cord blood, sorted and directly exposed to etoposide or MNU. Besides, CD34+ were expanded in-vitro in medium containing broad acting cytokines for 5 days prior genotoxic exposure. Sublethal doses were assessed by Alamar Blue assay. Propidium iodide staining and colony-forming unit assay (CFU) were used for cell cycle analysis and tracking of cell functionality.

Results

In vitro inhibitory concentrations were identified for human HSCs treated with etoposide (IC50 = 5 µM) and MNU (IC50 = 1 mM). Treatment of quiescent HSCs with lower genotoxin concentrations induces a cell cycle arrest in the G0/G1-phase, whereas higher concentrations activate apoptosis-related genes and completely abrogate further differentiation into colony-forming progenitors. In contrast, cycling HSCs exhibit an impaired proliferation, upregulation of autophagy-related genes, reduced proportions of viable CD34+ cells, and similar effects regarding differentiation capacity into colony-forming progenitors. However, cells exposed to lower genotoxin doses exhibit a higher regeneration capacity 3 days upon treatment.

Discussion

These results confirm that the DDR following DSB-induction differs between quiescent and cycling HSCs. Quiescent HSCs exhibit a stronger DDR, probably related to their longer lifespan. To avoid malignant transformation, it is necessary to preclude damage accumulation through cell cycle withdrawal and apoptosis. In contrast, more committed cells rather inline toward damage repair and restoration through activation of, for example, non-homologous end joining or mismatch repair genes.
Abstract 3 Generation of Myeloid Cells from Cord Blood-Derived CD34+ Cells for Therapeutic Intent
Authors: Kreuser Shannon , Davis Nicholas , Stoltzman Carrie , von Euw Erika , Delaney Colleen
Published: September 2022

Introduction

Macrophages and monocytes traffic to and infiltrate complex solid tumor microenvironments where conditions can promote an immunosuppressive phenotype in resident tumor-associated macrophages that hinder effective anti-tumor immune responses. Ongoing advances in cell engineering are being adapted to modify monocytes and macrophages into efficacious anti-tumor cell therapies. However, a limiting factor to this promising therapy has been cell numbers, since monocytes obtained from adult peripheral blood mononuclear cells do not expand ex vivo.

Objective

We are developing an expanded allogeneic, cryopreserved, off-the-shelf myeloid cell product for the treatment of solid tumors.

Methods

CD34+ cells isolated from pooled donor cord blood are the starting material for generation of myeloid cells. The process has three phases: (1) expansion of hematopoietic stem and progenitor cells, (2) continued expansion and differentiation into monocytes, and (3) differentiation of monocytes into mature macrophages. Cells are characterized before and after cryopreservation by immune phenotyping, morphology, and phagocytic capacity.

Results

The current culture method produces several thousand HLA-DR+ CD11b+ myeloid cells at both the monocyte and macrophage stage per starting CD34+ cell. These cells make up ~70% of the final cell product along with a potentially beneficial heterogeneous mix of additional myeloid-derived cells. Immunophenotyping demonstrates expression of canonical monocyte/macrophage markers, including CD14, CD86, and CD163. Cell morphology after macrophage differentiation is similar to that of peripheral blood-derived mature adult macrophages. Importantly, the final cell product can be cryopreserved with excellent recovery of viable cells post-thaw that are functional, as demonstrated by maintenance of phagocytic potential when compared with pre-cryopreservation function.

Discussion

This proprietary CD34+ cell expansion and directed differentiation platform results in the generation of therapeutically relevant numbers of functional myeloid cells. Furthermore, the ability to cryopreserve these cells, with demonstrated viability and function upon thaw, facilitates their use as an off-the-shelf cell therapy, with potential for faster and less expensive routes to treatments for solid tumors that have proven resistant to other cell therapies. Additional work is being done toward engineering these myeloid cells to express proteins to enhance a patient’s anti-tumor immune responses, whether these cells are used alone or in combination with other therapeutics.
Abstract 11 Outcome of Patients Treated with Umbilical Cord Blood and Homologous Serum Eye Drops
Authors: Buzzi Marina , Versura Piera
Published: September 2022

Introduction

Several authors have demonstrated the safety and efficacy of CBS eye drops in the treatment of severe DE with or without Sjogren’s syndrome (SS-I), ocular graft versus host disease (GVHD), persistent corneal epithelial defects, recurrent corneal erosions, chemical burns, and neurotrophic keratitis.

Objective

To compare the efficacy of cord blood serum (CBS) and adult donor peripheral blood serum (PBS) eye drops (prepared, standardized, and controlled in the Emilia Romagna Cord Blood Bank) in the treatment of severe dry eye disease (DED), a multicenter randomized, double masked, crossover clinical trial was designed.

Methods

Sixty patients diagnosed with severe DED associated with persistent corneal epithelial defects were randomized and equally assigned to group A (treated with CBS) or group B (treated with PBS) , eye drops administered 8 times/day for 1 month. Primary outcome was the pre-treatment and post-treatment change in corneal fluorescein staining. Secondary outcomes included the pretreatment and post-treatment change in ocular surface disease index (OSDI), questionnaire and Visual Analogue Score (VAS) of subjective symptoms, Schirmer I test, tear break-up time, and conjunctival staining. Patients with relapse in signs or symptoms after further 2 months switched to the remaining group for one additional month.

Results

Corneal staining was more significantly reduced after CBS treatment; both VAS and OSDI score reduction was observed in both groups, but group A reported significantly less grittiness and pain. Nineteen patients shifted in the crossover period. The within individual comparison confirmed a better recovery in the CBS treatment period. Epidermal growth factor, transforming growth factor, and platelet-derived growth factor content was associated with reduction of epithelial damage. Levels of interleukins were positively associated with symptoms decrease.

Discussion

DED signs improved after both CBS and PBS treatments with potential advantages of CBS for subjective symptoms and corneal damage reduction. In addition to the very important therapeutic value of EDHO products, considering the CB units not suitable for transplantation, we have identified novel non-wasteful clinical applications of those allogeneic biological products, resulting in an increase of ethical motivation of families generously donating CB for public benefit.
Abstract 12 Phase I Study of Cord Tissue Derived Mesenchymal Stromal Cells in COVID-19–Related Acute Respiratory Distress Syndrome
Authors: Kraft Bryan , Brown Linda , Scott Margaret , Vrionis Frank , Palumbo Ralph , Troy Jesse , Poehlein Emily , Cheatham Lynn , Chen Lingye , Kurtzberg Joanne , Manyara Raha , Hanafy Khalid , Shaz Beth
Published: September 2022

Introduction

SARS-CoV-2 infection results in the COVID-19 disease that caused a global pandemic. In severe cases, COVID-19 leads to acute respiratory distress syndrome (ARDS), due to direct lung injury and hyperinflammatory response. COVID-related ARDS treatment now includes remdesivir, dexamethasone, and anti-inflammatory monoclonal antibodies, which have decreased the mortality rate, yet patients continue to die from sepsis or multiorgan failure and new treatments are needed. The use of mesenchymal stromal cells (MSC) offers a unique therapeutic option that may shorten time to lung injury resolution through anti-inflammatory, immune-modulatory, and regenerative mechanisms.

Objective

The aim of this study was to test the safety of human cord tissue-derived MSCs (hCT-MSC) in patients with COVID-related ARDS. This study was funded by The Marcus Foundation.

Methods

In this phase I multisite study, 10 adults with COVID- related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg/dose, maximum dose 100 million cells with a post thaw viability ≥70%). Patients were excluded if they had evidence of multiorgan failure, immunodeficiency, or were receiving extracorporeal membrane oxygenation or not expected to survive more than 24 hours. The primary endpoint was short-term safety of hCT-MSC infusions. The secondary endpoints included 28-day survival and changes in the Murray Lung Injury Score.

Results

From August to November 2020, 10 patients (7 females, 3 males; 2 Black, 6 White, 2 other; 3 Hispanic or Latino), with a median age of 61.5 years (range 39-97), were enrolled at 2 sites. There were no infusion-related or study-related adverse events. The average cell dose administered was 0.94 ± 0.29 cells/kg, and average cell viability was 85% ± 11%; 5 of 30 (17%) doses were less than the study dose, and 29 of 30 (97%) met the ≥70% viability criteria. There were 28 non-serious adverse events in 3 unique patients and 2 serious adverse events in 2 unique patients, which were expected and deemed unrelated to the study product. Five patients died: 3 by day 28 and 2 by day 90. All deaths were determined to be unrelated to the hCT-MSCs. The Murray Lung Injury Score did not appear to change over the 28-day study period.

Discussion

hCT-MSCs infusions are safe in patients with COVID-related ARDS. Future studies determining their efficacy are warranted.
Abstract 13 A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke
Authors: Laskowitz Daniel , Poehlein Emily , Schpall Elizabeth , Willson Jeff , Wingard John , Freed Brian , Belagaje Samir , Khanna Anna , Duarte Daniel Vela , Volpi John , Marrotte Eric , Troy Jesse , Kurtzberg Joanne
Published: September 2022

Introduction

Stroke is the fifth leading cause of death in the United States. Tissue plasminogen activator and mechanical thrombectomy are the only effective treatments, but many patients are ineligible for these treatments.

Objective

The objective of this study was to determine whether an intravenous infusion of a non-HLA matched, unrelated donor umbilical cord blood (UCB) would improve functional outcomes.

Methods

We conducted a phase II multicenter, randomized (2:1), placebo controlled, double-blinded trial of UCB in adults with acute ischemic stroke. Patients had to have adequate immune function. Cord blood units were selected from U.S. public cord banks based on blood type, race, and cell dose. Study product was infused 3-10 days post stroke. Participants were randomized within strata of National Institutes of Health Stroke Scale Score (NIHSS) (<12 vs ≥12), and study center. The primary endpoint was change in Modified Rankin Scale (mRS) (baseline minus day 90). The study was powered at 80% (odds ratio of 2). Key secondary outcomes included functional independence at day 90 (mRS <2), NIHSS, the Barthel Index, infusion reactions, and adverse events.

Results

Seventy-nine participants were enrolled at 6 centers when the trial was closed early due to slow accrual related to COVID19; 73 participants (47 randomized to UCB) were included in the safety and efficacy analyses. The median (range) of the change in mRS was 1 (–2, 3) in UCB and 1 (–1, 4) in placebo. A shift analysis based on the proportional odds model showed an odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline mRS and randomization strata. No differences were observed on the key secondary outcomes. There were 17 mild infusion reactions (27.6% UCB; 15.4% placebo). The distribution of serious and non-serious adverse events was similar between arms.

Discussion

This study demonstrated the safety of infusing non-HLA matched UCB to adults with acute ischemic stroke. Feasibility and logistics were challenging. The primary efficacy endpoint did not demonstrate benefit in this underpowered sample size. In a secondary ad hoc analysis, a trend of improved functional outcomes at day 90 in recipients of UCB more than 5 days post stroke (Figure 1) could be explored in future trials.
Abstract 16 New Advanced Therapy Medicinal Products (ATMPs) in Medical Trials: A FamiCord Group Development Pipeline Update
Authors: Gerth André , Heike Opitz Constanze , Baran Tomasz , Oldak Tomasz
Published: September 2022

Introduction

Seventeen products in five countries are used in medical experiments and clinical trials. FamiCord Group, the leading stem cell bank in Europe and number 3 worldwide, is a listed biotech group consisting of the European biotech companies Vita 34 (Germany), P.B.K.M. (Poland), Crioestaminal (Portugal), Smart Cells (UK), and more than 30 other subsidiaries. FamiCord Group was founded in 2002 and is located in more than 35 countries in Europe and the Middle East. The Group is engaged in the storage of biological material and the manufacture, development, and approval of cell therapeutics for clinical use. More than 850,000 cryopreserved umbilical cord blood and tissue units and more than 4,200 patients treated with stem cells in clinical trials, experimental therapies, and standard therapies demonstrate the extraordinary expertise in stem cell banking and clinical application.

Objective

An overview of the Cell Therapy Pipeline with cell products from the FamiCord Group is shown in Table 1. ATMPs have been developed and manufactured in 3 synergistic R&D centers in Poland, Portugal, and Germany. Twenty preclinical and clinical trials are being conducted as part of in-house and consortia projects.

Methods

Selected new developments are presented in detail: BIOOPA for treatment of epidermolysis bullosa and CartiCure for treatment of cartilage damage in knee joint.

Results

The BIOOPA dressing for the treatment of epidermolysis bullosa is safe and effective, as no infections or necrosis were observed at the graft implant site during the follow-up period. These patients also reported reduced pain and improved quality of life. When used in orthopedics (CartiCure for cartilage damage), cord tissue-derived MSCs have been shown to be safe and fully integrated into the patient's cartilage, resulting in significant improvement in pain scores and quality of life.

Discussion

The trials presented demonstrate that allogeneic cell therapeutics are the future of regenerative medicine. Use of allogenic technology is the only way to overcome the limitations of the autologous approach: manufacturing process extensively scalable, drug available "off the shelf", applicable in all medical facilities, and economical manufacturing process due to unlimited scalability. Large pharmaceutical companies are investing significantly in this space.
Abstract 20 A Rapid and Sensitive IL-3-Based Assay Reveals How Various Pre-Processing Conditions Affect the Potency of Hematopoietic Stem Cells in Fresh Cord Blood Units
Authors: Dumont Nellie , Rouleau Pascal , Margaillan Guillaume , Laganière Josée
Published: September 2022

Introduction

Optimized procedures to collect, process, and store cord blood (CB) units are crucial to ensure stem cell product quality; however, current methods to assess hematopoietic stem cell (HSC) potency are time-consuming or lack sensitivity. Therefore, developing methods that rapidly and accurately portray HSC potency in fresh blood is important to help optimize clinical outcomes.

Objective

We sought to adapt to fresh CB a potency assay previously developed for HSCs contained in cryopreserved CB [Simard et al. Transfusion. 2019;59(6):2074-2083.]. We next used the assay to evaluate the impact of various CB processing conditions on HSC potency.

Methods

Fresh CB units were exposed to various pre-processing storage conditions (ie, temperature changes and various anticoagulants). Units were then analyzed at various time points up to 96 hours using traditional iShage and colony-forming assays, in parallel with the IL-3-based potency assay.

Results

For CB units maintained at room temperature (RT), the potency measured with the IL-3-based assay (ie, the proportion of IL-3-responsive CD34+ cells as measured by pStat5 activation) linearly decreased over time. A potency of 69% was observed when tested within 0-24 hours, compared with 56% and 40% in the 24-48–hour and the 48-72–hour groups, respectively. In addition, the IL-3-based assay showed that pre-processing storage at 4°C prevented this loss of HSC potency. By contrast, the HSC count by iShage and the CFU numbers remained unchanged with time or temperature variations.

Discussion

The newly developed IL3-based assay appears reliable and sensitive to characterize the potency of CD34+ cells in fresh CB. In addition, this assay indicated that HSC potency linearly decreased with time when CB units were maintained at RT but remained stable when units were stored at 4°C pre-processing. This temperature-related difference was not observed with traditional assays, indicating that the test could be a complementary tool to characterize CB units in research and operational settings.
Abstract 21 High-Throughput Blood Separation System for CD34+ Cell Isolation
Authors: Fedenko Shannon , McFetridge Calum , Milliron Hallie , Dobson Katherine
Published: September 2022

Introduction

Research into the therapeutic roles and clinical potential of CD34+ cells is growing [Weissman and Shizuru, Blood. 2008;112(9):3543-3553]. Accordingly, advances in cell isolation methods have risen to meet the research demand. Cord blood banks have a unique opportunity to source CD34+ cells because of their relatively high prevalence in cord blood [Dauber et al. Cytotherapy. 2011;13(4):449-458]. However, current isolation systems are not optimized for processing cord blood, and even blood-compatible systems typically require the blood to be processed before use. FerroBio (www.42bio.com) has developed a magnetic separation system that facilitates scalable, high-volume cell isolation from complex biological fluids, such as blood, without pre-processing. This technology is now being adapted for CD34+ cell isolation from cord blood.

Objective

In this study, the conditions in which magnetic beads efficiently bind target cells were explored. The objective of this work was to evaluate optimal blood mixing conditions to bring beads into contact with cells in suspension in the blood. This will allow unmodified cord blood units (CBUs) to flow directly into our apparatus.

Methods

The FerroBio separation process is comprised of three simple steps (Figure 1A). Here, conditions of step 1 were explored to maximize target cell recovery and viability. Variables included type of agitation equipment (Figure 1B), temperature, time, and relative air volume in the blood bag. Recovery and viability were measured via flow cytometry and calculated relative to unprocessed blood from the same CBU.

Results

Two mixing conditions were identified for maximum recovery of CD34+ cells (Figure 1C, blue bars). While not statistically different from each other, the Drum Roller method only requires one piece of standard equipment, is gentler, and can accommodate multiple CBUs simultaneously. No statistical difference in viability was observed in any conditions (90.7% ± 16.3%, n = 9). Increasing incubation time and the relative amount of air in the bag did not increase recovery (not shown).

Discussion

The FerroBio separator can streamline CD34+ cell isolation by processing high blood volumes in a fast, closed system with high recovery rates. Additional studies are under way to evaluate the functionality of the isolated CD34+ cells and efficiency of bead removal.
Abstract 25 ECTmatch: Optimizing Small-Scale Cord Blood Banking Through HLA Analysis
Authors: Dumont-Lagacé Maude , Feghaly Albert , Thauvette Gabrielle , Meunier Marie-Christine , Lemieux William , Fournier Diane , Richard Lucie , Lemieux Sébastien , Sauvageau Guy , Cohen Sandra
Published: September 2022

Introduction

Cord blood (CB) banks have had to rely on large inventories of CB units to try to serve the largest possible proportion of the population, all the while prioritizing collection of non-Caucasian ethnic groups. However, due to the high linkage disequilibrium of HLA genes and the high frequency of several HLA alleles in the population, CB banks contain hundreds of CB units that could be matched to the same patients, making the inventory somewhat redundant from a clinical standpoint.

Objective

ExCellThera developed ECTmatch, an algorithm dedicated to optimizing the selection of CB units based on in-depth HLA analysis in order to maximize the efficiency of the bank to suitably match the largest proportion of subjects within a small pool of donors.

Methods

The performance of ECTmatch was evaluated in a simulation aiming to select 100 CB units from the Héma-Québec CB bank that satisfied an arbitrary minimal cell content criteria of 120 × 107 TNC and 6 × 106 CD34+ cells (n = 2,987). Selection was performed to optimize matching for the Quebec population, with a minimal HLA-match of 5/8 for HLA-A, -B, -C, and -DRB1.

Results

ECTmatch provides a suitably matched donor for 71.5% of the Quebec population, compared with only 45.0% (±2.4%) with random selection. Because patients who require a CB transplant tend to have rarer HLAs, the performance of ECTmatch was evaluated for this specific subset of patients (n = 62). Again, ECTmatch outperformed random selection, by providing a donor for 54.8% of patients, compared with only 29.9% with random selection. Finally, while ECTmatch was developed to optimize CB selection specifically for the Quebec population, it still outperformed random selection for subjects from the other Canadian provinces or the USA.

Discussion

By selecting CB units based on HLA profiles, ECTmatch allows the creation of a highly useful inventory with a very low number of CB units. This approach to small-scale CB banking can be adapted to different population subsets and could be used to select a subset of CB units for pre-release for immediate clinical availability or for the creation of a pre-expanded CB inventory with maximal population coverage.
Abstract 26 HLA Analysis of the Australian Cord Blood Banks: How Diverse Are Donors?
Authors: Klamer Guy , Sue Jessica , Ko Kap-Hyoun , Trickett Annette , Johnson Phillip , Elwood Ngaire
Published: September 2022

Introduction

The network of public cord blood banks (CBB) in Australia, known as AusCord, is comprised of CBB located in Brisbane, Sydney, and Melbourne. The network stores almost 37,000 cord blood units (CBU) and has released more than 1,300 for transplantation.

Objective

The objectives of this study were (1) to determine the relative diversity of HLA allele subtypes, tissue types, and haplotypes at each of the banks and between the banks and (2) to identify common tissue types and haplotypes that could be utilized for clinical research and development of third party cell therapy products.

Methods

HLA data was obtained for 36,782 CBU stored in the AusCord inventory. To standardize data format, high-resolution typing was converted to 2-digit typing. HLA allele subtypes were ranked from most to least common. A subset of Indigenous Australian and Pacific Islander HLA allele subtypes was interrogated to determine whether increased frequency correlated with declared ethnicity. Tissue types were separated into CBU that had HLA-A, HLA-B, HLA-C, and HLA-DRB1 typing (21,815 total) and CBU that did not have HLA-C typing (36,782 total). CBU tissue types were interrogated in 3 separate groups: searchable, searched, and released inventory. Haplotypes were confirmed where maternal typing was available (3,105 CBU).

Results

Ethnicity screening for donors and strategic location of collection sites servicing ethnic minority communities resulted in banking of Indigenous Australian and Pacific Islander HLA. At a bank and network level, there was a similar frequency of specific HLA subtypes; however, when considering the tissue types, there was vast diversity (~75% unique with 8 allele typing). Whilst there is diversity, there was also a fraction of the inventory that exhibited repetitive tissue types that could be utilized for clinical research.

Discussion

The study demonstrates that cord blood collections are able to boost storage of diverse tissue types in, and unique to, a multicultural population such as Australia. This finding can guide policy development and funding, as well as operational decisions at the CBB. Furthermore, CBB are well positioned to support research and development activity aimed at discovery of new applications for cord blood units through supply of GMP grade cryopreserved products exhibiting common tissue types and haplotypes.
Abstract 28 Comparative Analysis of the Cord Blood Bank in Quebec
Authors: Lemieux William , Richard Lucie , Fournier Diane , Joron Susie , Sapir-Pichhadze Ruth , Lewin Antoine
Published: September 2022

Introduction

In the context of the regional diversity observed in the population of Quebec, the Héma-Québec Cord Blood Bank (HQ CBB) representation differs from that of the Héma-Québec Stem Cell Registry (HQ Registry). The Bank encourages registrants of non-European descent to promote diversity, and only collects from health centers around Montreal and Quebec cities because of proximity concerns.

Objective

In this study, we aimed to analyze allele frequencies in the HQ CBB to assess similarities and differences in reference to the HQ Registry.

Methods

The HQ Registry was previously typed using high-resolution genotyping. For the HQ CBB, ambiguous two-field HLA-A, -B, -C, and -DRB1 typing data were obtained from cord blood units. Statistical analyses were performed using the GENE[RATE] population analysis tools to estimate allele and haplotype frequencies by administrative region determined by registered postal codes. Hardy-Weinberg equilibrium was verified by the nested likelihood procedure. Finally, genetic distance was compared between the HQ Registry and the HQ CBB by region using Non-metric Multi-dimensional Scaling (NMDS).

Results

Because of the small sample size in certain regions, HLA frequency was analyzed for 7 of the 17 regions within the HQ CBB with typings from 11,472 cord blood units. The HLA allele frequencies were previously assessed for the Registry, with 3,806 donors originating from 14 administrative regions. The Hardy-Weinberg equilibrium was rejected at least in relation to one locus in 3 regions (Capitale-Nationale, Montreal, and Laval), which differs from the results obtained from the Registry, in which the equilibrium was rejected only for Montreal. As in the Registry, allele frequencies in the HQ CBB varied by region but had limited overlap with the HQ Registry. Two regions (Chaudière-Appalaches and Laval) demonstrated significant differences in allele frequencies as represented in the HQ Registry versus the HQ CBB.

Discussion

We observed differences in the Quebec population representation between the HQ CBB and the HQ Registry. This probably represents selection bias related to recruitment strategies and inclusion criteria. Importantly, the complementarity of these two stem cell sources could allow for a more diverse donor pool, and this understanding could also guide the recruitment strategies.
Abstract 30 Should Cord Blood Unit Distribution Patterns Impact Collection Strategies?
Authors: Frenet Emeline Masson , Sung Dorothy , Romeo Cynthia , Jimenez Alexandra , Weinberg Rona Singer
Published: September 2022

Introduction

The National Cord Blood Program has a large inventory of clinical cord blood units (CBUs) available for transplant (more than 60,000). As a small proportion is distributed each year, new collections should theoretically replenish the inventory, but it is unclear which characteristics should be prioritized for banking.

Objective

Our goal was to characterize distributed CBUs (in terms of cellularity, race/ethnicity, and match), compare them with the inventory, and devise a collection strategy.

Methods

Shipments from January 2015 to March 2022 were reviewed (n = 1,046). Race/ethnicity information on CBUs was obtained at the time of collection and was available for 55,934 stored CBUs and 1,020 distributed CBUs. It was also obtained for 394 recipients. HLA match was determined as HLA-A and B antigens and DRB1 allele match (/6), and allelic match as HLA-A, B, C, DRB1 allele match (/8). Total nucleated cells (TNC) and CD34 cells were counted at banking of the CBU, and cell doses (per kg of recipient’s weight) were calculated at shipment.

Results

The proportion of White Non-Hispanic (WNH) CBUs distributed (38%) was lower than what is present in the inventory (46%), but match levels were higher among these units (Figure 1A and 1B), with 55% of WNH CBUs being 5/8 or higher, vs 40% for minorities’ CBUs. Race match between CBU and recipient led to higher matched transplants, but 41% of race mismatched CBUs still reached 6/8 or higher allele match. The median TNC was 102 × 107 for stored CBUs and 167 × 107 for distributed CBUs (Figure 1C). Better matched units have been selected with lower cell contents (Figure 1D).

Discussion

CBUs broaden transplant options across ethnic groups, and much focus has been placed on collecting minorities’ CBUs. However, our analysis showed that WNH CBUs are still the largest distributed population, with higher allele match to the recipient (predicting better transplant outcomes), so these CBUs should not be excluded from collection strategies. From the data presented here, the goal for new collections should be to obtain CBUs with higher TNC and CD34 (spreading across all races and ethnicities). These would replenish the pool of high cellularity CBUs that are more often selected for transplant.