2018 ATS BEAR Cage Winning Proposal: Cell-Free DNA to Improve Lung Transplant Outcomes.
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ABSTRACT:
SUBMITTER: Agbor-Enoh S
PROVIDER: S-EPMC6515866 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:After dozens of clinical trials, there are still no Food and Drug Administration-approved drugs that improve mortality in acute respiratory distress syndrome (ARDS). These poor results may be caused in part by three unique pharmacological challenges presented by ARDS: (1) Patients with ARDS are fragile because of concomitant multiple organ dysfunction, so they do not tolerate off-target side effects of drugs; (2) inhaled drug delivery is impeded by the column of proteinaceous fluid covering the injured alveoli; and (3) ARDS is heterogeneous in its underlying pathophysiology, so targeting one pathway is unlikely to improve most patients. To address these three pharmacological problems, I present the development of pulmonary endothelium-targeted liposomes (PELs). PELs are approximately 100-nm drug carriers coated with antibodies that bind to the pulmonary capillary endothelium. In model organisms, intravenously injected PELs strongly concentrate drugs in alveoli, even in animal models displaying severe, spatially heterogeneous pathology similar to severe ARDS. By concentrating drugs in inflamed alveoli, PELs solve pharmacological challenge (1) above. By being obligate intravenous medications, they solve challenge (2). Finally, because PELs can be loaded with at least three drugs, they can solve challenge (3) with combination drug therapy. My colleagues and I are currently testing PELs loaded with numerous candidate drugs in mouse models of ARDS, and we are testing drug distribution in live pigs and ex vivo human lungs. We aim to use such preclinical validation to move PELs into a partnership with industry, and then to patients.
| S-EPMC5427718 | biostudies-literature
Project description: Not available
| S-EPMC7258650 | biostudies-literature
Project description:The sixth BMC Ecology Image Competition received more than 145 photographs from talented ecologists around the world, showcasing the amazing biodiversity, natural beauty and biological interactions found in nature. In this editorial, we showcase the winning images, as selected by our guest judge, Professor Zhigang Jiang from the Institute of Zoology of the Chinese Academy of Sciences, with help from the journal's editorial board. Enjoy!
| S-EPMC6407182 | biostudies-literature
Project description:ObjectiveThe effects of recipient body mass index (BMI) on waitlist strategies, waitlist outcomes, and post-transplant outcomes among adult patients listed for heart transplantation under the updated 2018 allocation system have not been well characterized.MethodsThe United Network of Organ Sharing data set between October 2015 and March 2021 was analyzed, and patients were grouped based on recipient BMI and whether listing occurred in the old (pre-October 2018) or new allocation system.ResultsListing strategies differed by BMI group, but trends of increased use of temporary mechanical support and decreased use of durable support remained among all BMI groups, except those with BMI > 35 kg/m2 . Waitlist outcomes improved among all BMI cohorts in the new allocation system, including among patients with BMI 30-34.9 and >35 kg/m2 , although patients with higher BMIs continued to have longer waitlist times. Post-transplant outcomes in the new allocation system are worse for patients with BMI > 30 kg/m2 (hazard ratio: 1.47; confidence interval: 1.19-1.82; p < .001).ConclusionsThe 2018 change to the heart transplant allocation system was associated with similar changes in the use of mechanical support for listing strategy across BMI ranges, except in the most obese, and improved waitlist outcomes across all BMI ranges. Post-transplant outcomes in the new allocation system are worse for patients with BMI > 30 kg/m2 compared to patients with BMI < 30 kg/m2 . These findings have important clinical implications for our understanding of the ongoing influence of BMI on waitlist courses and post-transplant outcomes among patients listed for heart transplantation.
| S-EPMC9320797 | biostudies-literature
Project description:In cage-free systems, laying hens must lay their eggs in the nests. Selecting layers based on nesting behavior would be a good strategy for improving egg production in these breeding systems. However, little is known about the genetic determinism of nest-related traits. Laying rate in the nests (LRN), clutch number (CN), oviposition traits (OT), and nest acceptance for laying (NAL) of 1,430 Rhode Island Red (RIR) hens and 1,008 White Leghorn (WL) hens were recorded in floor pens provided with individual electronic nests. Heritability and genetic and phenotypic correlations of all traits were estimated over two recording periods-the peak (24-43 weeks of age) and the middle (44-64 weeks of age) of production-by applying the restricted maximum likelihood method to an animal model. The mean oviposition time (MOT) ranged from 2 h 5 min to 3 h and from 3 h 35 min to 3 h 44 min after turning on the lights for RIR and WL hens, respectively. The mean oviposition interval ranged from 24 h 3 min to 24 h 16 min. All heritability and correlation estimates were similar for RIR and WL. Low to moderate heritability coefficients were estimated for LRN (0.04-0.25) and moderate to high heritability coefficients for CN and OT (0.27-0.68). CN and OT were negatively genetically correlated with LRN (-0.92 to -0.39) except during peak production for RIR (-0.30 to +0.43). NAL was weakly to moderately heritable (0.13-0.26). Genetic correlations between NAL and other traits were low to moderate (-0.41 to +0.44). In conclusion, CN and OT are promising selection criteria to improve egg production in cage-free systems. NAL can be also used to reduce the number of eggs laid off-nest in these breeding systems. However, variability in MOT must be maintained to limit competition for the nests.
| S-EPMC8136716 | biostudies-literature
Project description:Myelofibrosis etiology and transplant outcomes
| PRJNA769155 | ENA
Project description:Myelofibrosis etiology and transplant outcomes
| PRJNA769154 | ENA
Project description:PurposeReduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials.Patients and methodsTwo hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome.ResultsThere was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival.ConclusionThe intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.
| S-EPMC8078252 | biostudies-literature
Project description:The contribution of regulatory T cells (Treg) to the induction and maintenance of tolerance is well-recognized in rodents and may contribute to long-term human organ allograft survival. The therapeutic efficacy of adoptively-transferred Treg in promoting tolerance to organ allografts is well-recognized in mouse models. Early phase 1/2 clinical studies of Treg therapy have been conducted in patients with type-1 (autoimmune) diabetes and refractory Crohn's disease, and for inhibition of graft-versus-host disease following bone marrow transplantation with proven safety. The feasibility of adoptive Treg therapy in the clinic is subject to various parameters, including optimal cell source, isolation procedure, expansion, target dose, time of infusion, as well as generation of a GMP-cell product. Several phase 1/2 Treg dose-escalation studies are underway in organ transplantation. Recent evidence suggests that additional factors are critical to ensure Treg safety and efficacy in allograft recipients, including Treg characterization, stability, longevity, trafficking, concomitant immunosuppression, and donor antigen specificity. Accordingly, Treg therapy in the context of organ transplantation may prove more challenging in comparison to other prospective clinical settings of Treg immunotherapy, such as type-1 diabetes.
| S-EPMC5435383 | biostudies-literature
Project description:Nox2 is a ROS-generating enzyme, deficiency of which increases suppression by Tregs in vitro and in an in vivo model of cardiac remodeling. As Tregs have emerged as a candidate therapy in autoimmunity and transplantation, we hypothesized that Nox2 deficiency in Tregs in recipient mice may improve outcomes in a heart transplant model. We generated a potentially novel B6129 mouse model with Treg-targeted Nox2 deletion (Nox2fl/flFoxP3Cre+ mice) and transplanted with hearts from CB6F1 donors. As compared with those of littermate controls, Nox2fl/flFoxP3Cre+ mice had lower plasma levels of alloantibodies and troponin-I, reduced levels of IFN-γ in heart allograft homogenates, and diminished cardiomyocyte necrosis and allograft fibrosis. Single-cell analyses of allografts revealed higher absolute numbers of Tregs and lower CD8+ T cell infiltration in Nox2-deficient recipients compared with Nox2-replete mice. Mechanistically, in addition to a greater suppression of CD8+CD25- T effector cell proliferation and IFN-γ production, Nox2-deficient Tregs expressed higher levels of CCR4 and CCR8, driving cell migration to allografts; this was associated with increased expression of miR-214-3p. These data indicate that Nox2 deletion in Tregs enhances their suppressive ability and migration to heart allografts. Therefore, Nox2 inhibition in Tregs may be a useful approach to improve their therapeutic efficacy.
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