bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACT
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

AbstractCircadian 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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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) (&lt;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 &lt;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

Abstract

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

Abstract

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.