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Author(s):  
Sarah M Heston ◽  
Rebecca R Young ◽  
John S Tanaka ◽  
Kirsten Jenkins ◽  
Richard Vinesett ◽  
...  

Abstract Background Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are limited data on risk factors for CMV viremia and the safety of antiviral medications used to treat CMV in children. Methods We conducted a single-center retrospective study of children who underwent HSCT between 2000 and 2016. We used log-logistic regression to evaluate associations between clinical characteristics and CMV-free survival at 100 days after HSCT. We compared the incidences of laboratory-defined adverse events (AEs) during treatment with ganciclovir and foscarnet. Results Among 969 children, median (interquartile range) age was 6.5 (3.1, 11.5) years, and 80% underwent allogeneic HSCT. Two hundred forty-four (25%) children developed CMV viremia. Older age (OR=0.95; 95% CI: 0.92, 0.98), male sex (OR=0.71, 95% CI: 0.51, 0.99), non-Black non-white race (OR=0.56; 95% CI: 0.36, 0.87), umbilical cord blood donor source (OR=0.28; 95% CI: 0.08, 0.97), and CMV-seropositivity (R-/D+, OR=0.17, 95% CI: 0.07, 0.41; R+/D-, OR=0.14, 95% CI: 0.09, 0.21; R+/D+, OR=0.08, 95% CI: 0.04, 0.15) were associated with lower odds of 100-day CMV-free survival. Compared to foscarnet, ganciclovir was associated with lower incidences of thrombocytopenia (IRR: 0.38; 95% CI: 0.15, 0.97), electrolyte AEs (IRR: 0.42; 95% CI: 0.24, 0.75), endocrine AEs (IRR: 0.52; 95% CI: 0.34, 0.79), and renal AEs (IRR: 0.36; 95% CI: 0.19, 0.65). Conclusions CMV viremia occurred commonly among children after HSCT, and ganciclovir and foscarnet were associated with distinct toxicity profiles among children with CMV infection. These findings should be considered when developing CMV prevention and treatment strategies for children after HSCT.


2021 ◽  
Author(s):  
SHUANG TANG ◽  
Nannan Yang ◽  
Mingxi Yu ◽  
Shuo Wang ◽  
Xiangdong Hu ◽  
...  

Mitochondria transfer can rescue oocyte aging-related infertility. However, heterologous techniques are suspended due to heteroplasmy. Regarding autologous approaches, the donor source and manipulating procedures require further optimization. Here we propose a strategy using umbilical cord mesenchymal stem cells (UC-MSCs) as mitochondria donor cells and employing intercellular mitochondria transport as the transfer method. We cryopreserved UC-MSCs of the female pup. When the female aged, its UC-MSCs were induced into granulosa cells (iGCs). The zona-weakened GV oocytes were aggregated with autologous iGCs into iGC-oocyte complexes. After cultivation in GDF9-containing media, mitochondria migrated from iGCs into the GV oocyte via transzonal filopodia. The maturation rate, quality, and developmental potential of these oocytes were substantially increased. Furthermore, the birth rate after embryo transfer has been improved. This approach utilized noninvasive procedures to collect mitochondria donor cells and optimized mitochondria transfer manipulations, so may represent a promising advance towards the improvement of aging-related infertility.


Mobile DNA ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Phuc Leo H. Vo ◽  
Christopher Acree ◽  
Melissa L. Smith ◽  
Samuel H. Sternberg

AbstractBacterial transposons propagate through either non-replicative (cut-and-paste) or replicative (copy-and-paste) pathways, depending on how the mobile element is excised from its donor source. In the well-characterized E. coli transposon Tn7, a heteromeric TnsA-TnsB transposase directs cut-and-paste transposition by cleaving both strands at each transposon end during the excision step. Whether a similar pathway is involved for RNA-guided transposons, in which CRISPR-Cas systems confer DNA target specificity, has not been determined. Here, we apply long-read, population-based whole-genome sequencing (WGS) to unambiguously resolve transposition products for two evolutionarily distinct transposon types that employ either Cascade or Cas12k for RNA-guided DNA integration. Our results show that RNA-guided transposon systems lacking functional TnsA primarily undergo copy-and-paste transposition, generating cointegrate products that comprise duplicated transposon copies and genomic insertion of the vector backbone. Finally, we report natural and engineered transposon variants encoding a TnsAB fusion protein, revealing a novel strategy for achieving RNA-guided transposition with fewer molecular components.


2021 ◽  
Author(s):  
Phuc Leo Hong Vo ◽  
Christopher Acree ◽  
Melissa L. Smith ◽  
Samuel Henry Sternberg

Bacterial transposons propagate through either non-replicative (cut-and-paste) or replicative (copy-and-paste) pathways, depending on how the mobile element is excised from its donor source. In the well-characterized E. coli transposon Tn7, a heteromeric TnsA-TnsB transposase directs cut-and-paste transposition by cleaving both strands at each transposon end during the excision step. Whether a similar pathway is involved for RNA-guided transposons, in which CRISPR-Cas systems confer DNA target specificity, has not been determined. Here, we apply long-read, population-based whole-genome sequencing (WGS) to unambiguously resolve transposition products for two evolutionarily distinct transposon types that employ either Cascade or Cas12k for RNA-guided DNA integration. Our results show that RNA-guided transposon systems lacking functional TnsA primarily undergo copy-and-paste transposition, generating cointegrate products that comprise duplicated transposon copies and insertion of the vector backbone. Finally, we report natural and engineered transposon variants encoding a TnsAB fusion protein, revealing a novel strategy for achieving RNA-guided transposition with fewer molecular components.


2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Patrick Hagen ◽  
◽  
William Adams ◽  
Shruti Singh ◽  
Shuai Qin ◽  
...  

Allogeneic stem cell transplantation remains the only curative option for many hematological malignancies. Umbilical cord blood (UCB) is an alternate donor source with potentially increased morbidity in elderly patients. We evaluated outcomes in alternate donor sources, prior to the initiation of haploidentical transplantation at our institution, of matched unrelated donor (MUD) and UCB in elderly patients (mean age 64, range 60-75). One hundred and eighty-four patients were included (MRD: 57; MUD: 69; UCB: 58). There was no difference in acute or chronic graft versus host disease among donor sources (all p > .05). In this high-risk population, 128 (70%) had either a high disease risk index or high (>2) comorbidity index. Median progression free survival (PFS) was lowest among UCB (5.5 months; 95% CI 2.8-9.4) and MUD (5.6 months; 95% CI 3.7-17.7) as compared to MRD (18.3 months; 95% CI 8.4-64.8). On multivariable analysis, the rate of mortality was higher for UCB than MRD patients (1.88, 95% CI 1.04 – 3.37), but there was no difference between UCB and MUD (p = .61) or between MUD and MRD (p = .25). Conclusions were similar for PFS. Our experience shows that even in this high-risk elderly cohort, UCB continues to be a viable alternate donor source.


2021 ◽  
Author(s):  
Clare Gietzel ◽  
Jacques Duquette ◽  
Lillian McGilp ◽  
Jennifer Kimball

AbstractNorthern wild rice (NWR; Zizania palustris L.) is a wind-pollinated, annual, aquatic grass that grows naturally in the Great Lakes Region (GLR) of the United States and Canada, and is also cultivated in flooded paddies, predominantly in California and Minnesota. A better understanding of pollen-mediated gene flow is needed within the species for both conservation and breeding efforts as cultivation occurs within the species natural range and spatially-isolated, paddy structures are limited within breeding programs. Widely cited pollen travel research in NWR demonstrated that pollen could travel at least 3200m. However, a population segregating for male sterility was used as the pollen recipient in the study and was determined to not be adequate for NWR pollen travel studies. Here, we present the characterization of a recessive white male floret (WMF) population in contrast to the dominant, purple male floret (PMF) color of cultivated NWR along with estimates of pollen-mediated gene flow in a cultivated paddy setting. Studies conducted in 2018 and 2019 revealed that the primary amount of pollen-mediated gene flow occurred within the first 7m from the PMF donor source with no gene flow detected past 63m. These results suggest that the likelihood of pollen-mediated gene flow between cultivated NWR and natural stands remains low. We also identified a strong linkage between male floret, auricle, and culm color. This study demonstrates that the WMF trait is an excellent candidate for use in pollen-mediated gene flow studies in NWR.


2021 ◽  
Vol 12 ◽  
pp. 204062072110437
Author(s):  
Silvia Park ◽  
Tong Yoon Kim ◽  
Jong Hyuk Lee ◽  
Joon yeop Lee ◽  
Gi June Min ◽  
...  

Introduction: Donor lymphocyte infusion (DLI) is one of the effective options for post-transplant disease control of myelodysplastic syndrome (MDS). Its success or failure depends on the induction of antitumor immune reactions, durability of clinical responses, and severity of unwanted toxicities mainly from graft- versus-host disease (GVHD). Methods: By analyzing 61 patients receiving DLI for post-transplant MDS relapse, we assessed treatment outcomes and affecting factors, especially focusing on the level of relapse (hematological, molecular, and imminent relapse). Results: The response rate (42.1%, 36.4%, 72.7%), and overall survival (OS) at 2 years (27.8%, 45.5%, 70.1%) were different for each relapse level with imminent relapse group showing the most promising results. For OS, response to DLI or pre-DLI chemotherapy, and time to relapse were independent prognostic factors. Meanwhile, post-DLI GVHD and time to relapse were independently predictive for DLI response; post-DLI GVHD was predictive for DLI response, but not for OS, suggesting a potential detrimental impact of GVHD on survival. The incidence of GVHD and GVHD-related deaths were 37.7% and 10.0%, respectively, and CD3+ cell doses triggering GVHD tended to be lower in cases with haploidentical donor or imminent relapse. Conclusion: Despite being limited by small number of cases and its retrospective nature, this study again demonstrated the therapeutic effects of DLI in relapsed MDS, and that earlier detection and intervention at lower level relapse might possibly be associated with better results. Furthermore, we propose that tailored cell dosing schedule based on relapse level and donor source may be helpful in minimizing fatal GVHD.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Shaik Rashid ◽  
Matthew Carabasi ◽  
Joanne Filicko-O'Hara ◽  
John L. Wagner ◽  
William O'Hara ◽  
...  

Introduction: Hematopoietic stem cell transplant (HSCT) remains the only curative therapy for myelofibrosis (MF). However as compared to other hematologic malignancies, HSCT for MF is associated with an increased risk of graft failure due to a limited marrow niche and splenic sequestration of allogeneic progenitors. We report on engraftment and other outcomes in 12 consecutive patients with MF undergoing matched (M-HSCT) and haplo-identical (HI-HSCT) utilizing a two-step T cell-tolerization approach. Methods: Regardless of donor source, all patients were conditioned with our institution's two-step approach. After reduced intensity conditioning consisting of fludarabine, 2 Gy total body irradiation, thiotepa (n=3) OR busulfan (n=8), and in 1 case myeloablative conditioning with 12 Gy total body irradiation, patients received an unmanipulated donor lymphocyte product (DLI) containing 2 x 108/kg CD3+ cells. After 2 days, cyclophosphamide (CY) 60 mg/kg was administered daily x 2 for bidirectional T cell tolerization. One day after CY completion, a CD34-selected stem cell product was infused. All patients received mycophenolate mofetil and tacrolimus beginning on d-1. Pre-conditioning splenic radiation was added starting in 2017 to decrease splenic sequestration of donor cells. This change affected the last six patients in the analysis. Results: Six patients had primary MF and six patients had secondary MF. Donor source was a HLA matched (n=5, median age 54y, range 44-65) or haploidentical (n=7, median age 66y, range 47-67) relative. Eight patients received pre-HSCT radiation or splenectomy. Outcome data is summarized in the table. Median follow-up is 29 (range 6-95.6) months. Median time to neutrophil and platelet engraftment was 12 (range 9-13) days and 19 (13-40) days respectively. Patients undergoing pre-HSCT splenic therapy recovered platelets more rapidly than those without, median 19 vs 27 days, (p=0.059). All patients ultimately achieved 100% donor chimerism. While there was a trend in the M-HSCT group for higher donor T cell chimerism at d+28 in patients undergoing pre-HSCT splenic therapy, (p=0.083), donor source had the most significant impact on the pace of donor chimerism recovery. All 4 DLIs given in this group for fluctuating donor T cell chimerism occurred in M-HSCT recipients. At d+28 median donor T cell chimerism was 100% (range 91-100) in HI-HSCT versus 92% (range 67-100%) in M-HSCT recipients, (p=0.037). Probability of OS at 3 years was 90%. No patient receiving splenic therapy experienced disease progression. Two patients who received DLI experienced graft versus host disease (GVHD), grade 3 acute GVHD in one and extensive chronic GVHD in the other. Conclusion: HSCT using the two-step approach is associated with rapid engraftment and excellent survival in patients with MF. Pre-HSCT splenic therapy was associated with more rapid platelet recovery. Unlike HI-HSCT, M-HSCT patients receiving RIC conditioning experienced initial fluctuating donor T-cell chimerism, a finding worth further exploration in larger trials. Table Disclosures Gergis: Jazz: Other: Ad board, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Mesoblast: Other: Ad Board; Incyte: Speakers Bureau; Merck: Speakers Bureau. Flomenberg:Tevogen: Consultancy, Honoraria.


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