Publications by authors named "Petr Sedláček"

105 Publications

The underexplored role of diverse stress factors in microbial biopolymer synthesis.

Bioresour Technol 2021 Apr 28;326:124767. Epub 2021 Jan 28.

Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28/VI, 8010 Graz, Austria; ARENA Arbeitsgemeinschaft für Ressourcenschonende & Nachhaltige Technologien, Inffeldgasse 21b, 11 8010 Graz, Austria.

Polyhydroxyalkanoates (PHA) are microbial polyesters which, apart from their primary storage role, enhance the stress robustness of PHA accumulating cells against various stressors. PHA also represent interesting alternatives to petrochemical polymers, which can be produced from renewable resources employing approaches of microbial biotechnology. During biotechnological processes, bacterial cells are exposed to various stressor factors such as fluctuations in temperature, osmolarity, pH-value, elevated pressure or the presence of microbial inhibitors. This review summarizes how PHA helps microbial cells to cope with biotechnological process-relevant stressors and, vice versa, how various stress conditions can affect PHA production processes. The review suggests a fundamentally new strategy for PHA production: the fine-tuned exposure to selected stressors, which might be used to boost PHA production and even to tailor their structure.
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http://dx.doi.org/10.1016/j.biortech.2021.124767DOI Listing
April 2021

Edible Films from Carrageenan/Orange Essential Oil/Trehalose-Structure, Optical Properties, and Antimicrobial Activity.

Polymers (Basel) 2021 Jan 21;13(3). Epub 2021 Jan 21.

Department of Plant Origin Food Sciences, Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho tr. 1946/1, 612 42 Brno, Czech Republic.

The research aim was to use orange essential oil and trehalose in a carrageenan matrix to form edible packaging. The edible packaging experimentally produced by casting from an aqueous solution were evaluated by the following analysis: UV-Vis spectrum, transparency value, transmittance, attenuated total reflectance Fourier-Transform spectroscopy (FTIR), scanning electron microscopy (SEM) and antimicrobial activity. The obtained results showed that the combination of orange essential oil with trehalose decreases the transmittance value in the UV and Vis regions (up to 0.14% ± 0.02% at 356 nm), meaning that produced films can act as a UV protector. Most produced films in the research were resistant to Gram-positive bacteria ( subsp. ), though most films did not show antibacterial properties against Gram-negative bacteria and yeasts. FTIR and SEM confirmed that both the amount of carrageenan used and the combination with orange essential oil influenced the compatibility of trehalose with the film matrix. The research showed how different combinations of trehalose, orange essential oils and carrageenan can affect edible film properties. These changes represent important information for further research and the possible practical application of these edible matrices.
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http://dx.doi.org/10.3390/polym13030332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864528PMC
January 2021

Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.

J Clin Oncol 2021 Feb 17;39(4):295-307. Epub 2020 Dec 17.

Goethe University, University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Frankfurt am Main, Germany.

Purpose: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.

Patients And Methods: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).

Results: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; < .0001) and 0.02 (95% CI, < 0.01 to 0.05; = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.

Conclusion: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
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http://dx.doi.org/10.1200/JCO.20.02529DOI Listing
February 2021

Multiscale Experimental Evaluation of Agarose-Based Semi-Interpenetrating Polymer Network Hydrogels as Materials with Tunable Rheological and Transport Performance.

Polymers (Basel) 2020 Oct 31;12(11). Epub 2020 Oct 31.

Faculty of Chemistry, Brno University of Technology, Purkynova 118, 61200 Brno, Czech Republic.

This study introduces an original concept in the development of hydrogel materials for controlled release of charged organic compounds based on semi-interpenetrating polymer networks composed by an inert gel-forming polymer component and interpenetrating linear polyelectrolyte with specific binding affinity towards the carried active compound. As it is experimentally illustrated on the prototype hydrogels prepared from agarose interpenetrated by poly(styrene sulfonate) (PSS) and alginate (ALG), respectively, the main benefit brought by this concept is represented by the ability to tune the mechanical and transport performance of the material independently via manipulating the relative content of the two structural components. A unique analytical methodology is proposed to provide complex insight into composition-structure-performance relationships in the hydrogel material combining methods of analysis on the macroscopic scale, but also in the specific microcosms of the gel network. Rheological analysis has confirmed that the complex modulus of the gels can be adjusted in a wide range by the gelling component (agarose) with negligible effect of the interpenetrating component (PSS or ALG). On the other hand, the content of PSS as low as 0.01 wt.% of the gel resulted in a more than 10-fold decrease of diffusivity of model-charged organic solute (Rhodamine 6G).
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http://dx.doi.org/10.3390/polym12112561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693122PMC
October 2020

Features and outcome of chronic myeloid leukemia at very young age: Data from the International Pediatric Chronic Myeloid Leukemia Registry.

Pediatr Blood Cancer 2021 01 8;68(1):e28706. Epub 2020 Oct 8.

Medical Faculty, Pediatric Hematology-Oncology, Technical University of Dresden, Dresden, Germany.

Introduction: Chronic myeloid leukemia (CML) is rare in the first two decades of life comprising only 3% of newly diagnosed pediatric and adolescent leukemias. We studied the epidemiologic and clinical features of patients with CML diagnosed at younger than 3 years of age and evaluated treatment and long-term outcome.

Method: Data from the International Pediatric I-BFM/CML Registry were retrospectively analyzed using the European LeukemiaNet criteria of the year 2006. Characteristics and treatment outcome of patients <3 years old at diagnosis were evaluated from standardized forms.

Results: Twenty-two patients (n = 22/479; 4.6%, male/female:14/8) were enrolled with a median age of 22 months (range, 10-34 m). Major symptoms comprised asthenia (30%), fever (30%), abdominal pain (20%), extramedullary signs (14%), hemorrhage (5%), and weight loss (5%). The extramedullary signs were specified in eight children: blueberry muffin (n = 1), sudden swollen abdomen (n = 1), sustained vomiting (n = 1), and cervical and inguinal lymph nodes (n = 5). Two of five children with cervical and inguinal lymph nodes were categorized as accelerated phase. Overall, 19 of 22 (86%) children were diagnosed in chronic phase, while the remaining three patients were in advanced phase. Median follow-up was 78 months (range, 7-196 m). Twenty-one out of 22 patients initially received imatinib, while one child received IFN + ARA-C. Imatinib was changed to second-line tyrosine kinase inhibitors (TKIs) in 29% of cases. During follow-up, 41% patients underwent stem cell transplantation (SCT). While on TKI, major molecular response (MMR) was achieved in 48% of children. Among the remaining patients, 21% are alive on TKI without MMR and 22% achieved complete molecular response following SCT. Twenty-one of 22 (95%) children are alive, while one patient died of posttransplant complications.

Conclusion: This report demonstrates for the first time the efficacy and long-term effects of upfront imatinib in the so far largest cohort of children with CML diagnosed at very young age.
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http://dx.doi.org/10.1002/pbc.28706DOI Listing
January 2021

Lymphoblastic predominance of blastic phase in children with chronic myeloid leukaemia treated with imatinib: A report from the I-CML-Ped Study.

Eur J Cancer 2020 09 13;137:224-234. Epub 2020 Aug 13.

Inserm CIC 1402, University Hospital, Poitiers, France.

Background: Chronic myeloid leukaemia (CML) is a rare disease in children. The frequency and outcome of children evolving to accelerated phase (AP) or blastic phase (BP) under treatment with imatinib is unknown. The aim of the current study is to assess the incidence of progression from CML in chronic phase with imatinib frontline in a paediatric setting and describe the management and outcome of these patients.

Patients And Methods: In the I-CML-Ped Study database (www.clinicaltrials.gov, #NCT01281735), 19 of 339 paediatric patients in chronic phase treated with imatinib in the frontline evolved to CML-AP or CML-BP.

Results: With a median follow-up of 38 months (range: 2-190 months), the cumulative incidence of progression at 1 and 3 years was 3% (confidence interval [CI] 95%: 1-5%) and 7% (CI 95%: 4-11%), respectively. We observed a large predominance of lymphoid-BP (70%) over myeloid-BP (30%) with imatinib in frontline therapy. Sixteen patients underwent haematopoietic stem cell transplantation, and eight were treated with a tyrosine kinase inhibitor after transplant. Only the transplanted patients are alive. The 5-year overall survival rate of children with CML-AP/BP is 44%, with no statistical difference between the lymphoid-BP and myeloid-BP outcome.

Conclusion: Children evolving to AP or BP under treatment with imatinib have a very poor prognosis with an overall survival under 50%, much worse than children with advanced phase at diagnosis.
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http://dx.doi.org/10.1016/j.ejca.2020.06.024DOI Listing
September 2020

The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG.

Bone Marrow Transplant 2021 Jan 4;56(1):257-266. Epub 2020 Aug 4.

St Anna Children's Hospital, Universitätsklinik für Kinder- und Jugendheilkunde, Medizinische Universität Wien, Vienna, Austria.

Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13 ± 2% and 17 ± 4% (p = NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60 ± 2% vs. 42 ± 5%, p < 0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9 ± 1% vs. 23 ± 4%, p < 0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.
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http://dx.doi.org/10.1038/s41409-020-01014-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796856PMC
January 2021

Ageing effect on conazole fungicide bioaccumulation in arable soils.

Chemosphere 2021 Jan 30;262:127612. Epub 2020 Jul 30.

Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Kamenice 753/5, Brno, 625 00, Czech Republic. Electronic address:

Widely used conazole fungicides (CFs) belong to the most frequently detected pesticides in Central European arable soils. However, data on their environmental behaviour and bioavailability to soil organisms are surprisingly scarce. In the present laboratory microcosm study prochloraz, tebuconazole, epoxiconazole and flusilazole were applied to 12 different agricultural soils at background levels. Bioaccumulation to earthworm E. andrei and lettuce L. sativa roots and leaves was evaluated in non-aged (biota exposure after addition of pesticides) and aged (exposure started three months later) systems. In contrast with expectations from ageing effect (decrease of bioavailability), bioaccumulation in E. andrei was both reduced and enhanced after ageing depending on soil properties. The reduction of bioaccumulation correlated positively to the percentage of clay but negatively to soil organic matter. The affinity of compost worm E. andrei towards organic matter where hydrophobic pesticide molecules are sorbed is discussed as a possible explanation. An apparent effect of ageing (reduction of bioavailability) was particularly observed in lettuce roots, where bioaccumulation was significantly reduced in time. However, bioaccumulation in leaves changed ambiguously in aged variants among CFs, possibly as a combined result of bioconcentration, dilution by plant growth and metabolism. This study brings first insights into how the bioaccumulation of conazole fungicides is affected by sequestration in agricultural soils. The results indicate that in complex systems, the ageing is not necessarily connected with decrease of bioaccumulation.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127612DOI Listing
January 2021

Production of polyhydroxyalkanoates (PHA) by a thermophilic strain of Schlegelella thermodepolymerans from xylose rich substrates.

Bioresour Technol 2020 Nov 22;315:123885. Epub 2020 Jul 22.

Department of Food Chemistry and Biotechnology, Faculty of Chemistry, Brno University of Technology, Purkynova 118, 612 00 Brno, Czech Republic. Electronic address:

The aim of this work was to investigate the thermophilic bacterium Schelegelella thermodepolymerans DSM 15344 in terms of its polyhydroxyalkanoates (PHA) biosynthesis capacity. The bacterium is capable of converting various sugars into PHA with the optimal growth temperature of 55 °C; therefore, the process of PHA biosynthesis could be robust against contamination. Surprisingly, the highest yield was gained on xylose. Results suggested that S. thermodepolymerans possess unique xylose metabolism since xylose is utilized preferentially with the highest consumption rate as compared to other sugars. In the genome of S. thermodepolymerans DSM 15344, a unique putative xyl operon consisting of genes responsible for xylose utilization and also for its transport was identified, which is a unique feature among PHA producers. The bacterium is capable of biosynthesis of copolymers containing 3-hydroxybutyrate and also 3-hydroxyvalerate subunits. Hence, S.thermodepolymerans seems to be promising candidate for PHA production from xylose rich substrates.
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http://dx.doi.org/10.1016/j.biortech.2020.123885DOI Listing
November 2020

Adsorption of epoxiconazole and tebuconazole in twenty different agricultural soils in relation to their properties.

Chemosphere 2020 Dec 16;261:127637. Epub 2020 Jul 16.

Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Kamenice 753/5, Brno, 625 00, Czech Republic. Electronic address:

Conazole fungicides are currently used pesticides with considerable chronic toxicity and ecotoxicity that are also on EU list for substitution. They enter the soil forming short- or long-term residues. In this study two of their representatives, epoxiconazole (EPC) and tebuconazole (TBC), have been tested with 20 soils from the Czech Republic for their adsorption. Adsorption, by means of Kd coefficients, was compared to "basic" (TOC, pH, clay …) and "advanced" (surface area, minerals ..) soil properties. After doing multivariate analysis of the variables it was apparent that adsorption of both pesticides was highly associated with pH (negatively correlated), and less associated with soil organo-mineral complex (TOC, clay and surface area) and C and N in soil organic matter (OM). Particle sizes or cation exchange capacity (CEC) did not show correlation with adsorption, but showed an association in multidimensional space in factor analysis (FA). Some correlations were revealed between EPC adsorption and soil organic matter parameters. Recalculating Kd to K and to Gibb's free energy (ΔG) and its values indicated that the adsorption of EPC and TBC is mainly weak physical adsorption - partitioning. Also, ΔG values gave better correlation with pH than Kd. Surface area impacted EPC adsorption. From the several soil minerals, kaolinite showed EPC and TBC adsorption. EPC adsorption was not highly influenced with pH changes compared to TBC. The number and types of H-bonds with molecular geometry govern the sorption, which might crucially affect leachibility in soil, and this may indicate that TBC is more leachable than EPC for the same soil.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127637DOI Listing
December 2020

Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults.

Blood 2020 09;136(10):1201-1211

Department of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.
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http://dx.doi.org/10.1182/blood.2020005590DOI Listing
September 2020

Introducing the Newly Isolated Bacterium sp. H1 as an Auspicious Thermophilic Producer of Various Polyhydroxyalkanoates (PHA) Copolymers-2. Material Study on the Produced Copolymers.

Polymers (Basel) 2020 Jun 5;12(6). Epub 2020 Jun 5.

Faculty of Chemistry, Brno University of Technology, Purkynova 118, 612 00 Brno, Czech Republic.

sp. H1 is a promising, moderately thermophilic, novel Gram-positive bacterium capable of the biosynthesis of polyhydroxyalkanoates (PHA) with tunable monomer composition. In particular, the strain is able to synthesize copolymers of 3-hydroxybutyrate (3HB), 4-hydroxybutyrate (4HB) and 3-hydroxyvalerate (3HV) with remarkably high 4HB and 3HV fractions. In this study we performed an in-depth material analysis of PHA polymers produced by sp. H1 in order to describe how the monomer composition affects fundamental structural and physicochemical parameters of the materials in the form of solvent-casted films. Results of infrared spectroscopy, X-ray diffractometry and thermal analysis clearly show that controlling the monomer composition enables optimization of PHA crystallinity both qualitatively (the type of the crystalline lattice) and quantitatively (the overall degree of crystallinity). Furthermore, resistance of the films against thermal and/or enzymatic degradation can also be manipulated by the monomer composition. Results of this study hence confirm sp. H1 as an auspicious candidate for thermophilic production of PHA polymers with material properties that can be tuned together with their chemical composition by the corresponding adjustment of the cultivation process.
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http://dx.doi.org/10.3390/polym12061298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362046PMC
June 2020

Introducing the Newly Isolated Bacterium sp. H1 as an Auspicious Thermophilic Producer of Various Polyhydroxyalkanoates (PHA) Copolymers-1. Isolation and Characterization of the Bacterium.

Polymers (Basel) 2020 May 29;12(6). Epub 2020 May 29.

Faculty of Chemistry, Brno University of Technology, Purkynova 118, 612 00 Brno, Czech Republic.

Extremophilic microorganisms are considered being very promising candidates for biotechnological production of various products including polyhydroxyalkanoates (PHA). The aim of this work was to evaluate the PHA production potential of a novel PHA-producing thermophilic Gram-positive isolate sp. H1. This organism was capable of efficient conversion of glycerol into poly(3-hydroxybutyrate) (P3HB), the homopolyester of 3-hydroxybutyrate (3HB). In flasks experiment, under optimal cultivation temperature of 45 °C, the P3HB content in biomass and P3HB titers reached 55.31% of cell dry mass and 2.03 g/L, respectively. Further, the isolate was capable of biosynthesis of PHA copolymers and terpolymers containing high molar fractions of 3-hydroxyvalerate (3HV) and 4-hydroxybutyrate (4HB). Especially 4HB contents in PHA were very high (up to 91 mol %) when 1,4-butanediol was used as a substrate. Based on these results, it can be stated that sp. H1 is a very promising candidate for production of PHA with tailored material properties.
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http://dx.doi.org/10.3390/polym12061235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362256PMC
May 2020

Novel unexpected functions of PHA granules.

Appl Microbiol Biotechnol 2020 Jun 17;104(11):4795-4810. Epub 2020 Apr 17.

Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28/VI, 8010, Graz, Austria.

Polyhydroxyalkanoates (PHA), polyesters accumulated by numerous prokaryotes in the form of intracellular granules, have been for decades considered being predominantly storage molecules. However, numerous recent discoveries revealed and emphasized their complex biological role for microbial cells. Most of all, it was repeatedly reported and confirmed that the presence of PHA granules in prokaryotic cells enhances stress resistance and robustness of microbes against various environmental stress factors such as high or low temperature, freezing, oxidative, and osmotic pressure. It seems that protective mechanisms of PHA granules are associated with their extraordinary architecture and biophysical properties as well as with the complex and deeply interconnected nature of PHA metabolism. Therefore, this review aims at describing novel and unexpected properties of PHA granules with respect to their contribution to stress tolerance of various prokaryotes including common mesophilic heterotrophic bacteria, but also extremophiles or photo-autotrophic cyanobacteria. KEY POINTS: • PHA granules present in bacterial cells reveal unique properties and functions. • PHA enhances stress robustness of bacterial cells.
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http://dx.doi.org/10.1007/s00253-020-10568-1DOI Listing
June 2020

Curability and transferability of atopy with allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2020 07 30;55(7):1282-1289. Epub 2020 Mar 30.

University of Calgary, Calgary, AB, Canada.

Atopy is excessive production of IgE in response to allergens. We evaluated in patients undergoing allogeneic hematopoietic cell transplantation (HCT) the following hypotheses: (1) Atopy is "curable" in atopic patients receiving HCT from a nonatopic donor (D-R+), and (2) Atopy is transferable from atopic donors to nonatopic recipients (D+R-). Atopic patients with atopic donors (D+R+) and non-atopic patients with non-atopic donors (D-R-) served as controls. We measured levels of multiallergen-specific IgE (A-IgE, atopy defined as ≥0.35 kU/L) in sera from 54 patients and their donors pre HCT and from the patients at ≥2 years post HCT. Only 7/12 (58%) D- R+ patients became nonatopic after HCT. Only 1/11 (9%) D+R- patients became atopic. Eleven of 13 (85%) D-R- patients remained nonatopic. Unexpectedly, 11/18 (61%) D+R+ patients became nonatopic. In conclusion, contrary to our hypothesis and previous reports, the "cure" of atopy may occur in only some D-R+ patients and the transfer of atopy may occur rarely. The "cure" may not be necessarily due to the exchange of atopic for nonatopic immune system, as the "cure" may also occur in D+R+ patients.
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http://dx.doi.org/10.1038/s41409-020-0876-7DOI Listing
July 2020

Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies.

Bone Marrow Transplant 2020 10 20;55(10):1996-2007. Epub 2020 Mar 20.

Great Ormond Street Hospital, London, UK.

Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m/day (7.7%), 12 g/m/day (35.4%), or 14 g/m/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.
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http://dx.doi.org/10.1038/s41409-020-0869-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515850PMC
October 2020

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study.

Bone Marrow Transplant 2020 08 17;55(8):1540-1551. Epub 2020 Mar 17.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University Frankfurt, Frankfurt, Germany.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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http://dx.doi.org/10.1038/s41409-020-0854-0DOI Listing
August 2020

Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant 2020 06 6;55(6):1126-1136. Epub 2020 Feb 6.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University, Frankfurt am Main, Germany.

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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http://dx.doi.org/10.1038/s41409-020-0818-4DOI Listing
June 2020

Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children.

Br J Haematol 2020 05 3;189(4):745-750. Epub 2020 Feb 3.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Universities of Medical University Hannover, Hannover, Germany.

Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0·0001). Achievement of a subsequent remission impacted survival (P = <0·0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0·046) and donor choice (matched family vs. matched unrelated donor, P = 0·029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.
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http://dx.doi.org/10.1111/bjh.16441DOI Listing
May 2020

Application of osmotic challenge for enrichment of microbial consortia in polyhydroxyalkanoates producing thermophilic and thermotolerant bacteria and their subsequent isolation.

Int J Biol Macromol 2020 Feb 16;144:698-704. Epub 2019 Dec 16.

Faculty of Chemistry, Brno University of Technology, Purkynova 118, 612 00 Brno, Czech Republic. Electronic address:

Polyhydroxyalkanoates are microbial polyesters which are considered being biological alternatives to petrochemical polymers. Extremophiles, such as thermophilic PHA producers, hold promise to improve competitiveness of PHA production process. Therefore, this work aimed at isolation of new strains, which could produce PHA under elevated temperature. Since traditional Nile red staining of colonies provided false positive results in thermophiles, we developed a novel strategy of enriching microbial consortia by PHA producers. This so called "osmoselective strategy" is based on application of osmotic challenge by sudden exposition of the mixed microbial culture to hypertonic and subsequently to hypotonic conditions; moreover, this strategy relies on the fact that PHA protect bacteria from negative effects of rapid fluctuations in osmotic pressure. In combination with fast and reliable ATR-FTIR inspection of selected colonies for presence of PHA, we were able to isolate several promising thermophilic or thermotolerant PHA producing strains belonging to the genera Bacillus, Aneurinibacillus and Chelatococcus, which indeed deserves further investigation to evaluate their potential for industrial production of PHA.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.12.128DOI Listing
February 2020

Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement.

Front Immunol 2019 18;10:2194. Epub 2019 Sep 18.

Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia.

Mutations in the Sterile alpha motif domain containing 9 () gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in (c.2471 G>A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel mutation was confirmed experimentally. Expression of mutant caused a significant decrease in proliferation and increase in cell death of the transfected cells. We describe a novel mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with mutations and multisystem involvement.
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http://dx.doi.org/10.3389/fimmu.2019.02194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759462PMC
November 2020

Hematopoietic stem cell transplantation for children with acute myeloid leukemia-results of the AML SCT-BFM 2007 trial.

Leukemia 2020 02 2;34(2):613-624. Epub 2019 Oct 2.

Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Düsseldorf, Düsseldorf, Germany.

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).
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http://dx.doi.org/10.1038/s41375-019-0584-8DOI Listing
February 2020

Biotechnological Production of Poly(3-Hydroxybutyrate--4-Hydroxybutyrate-3-Hydroxyvalerate) Terpolymer by sp. DSM 19379.

Bioengineering (Basel) 2019 Aug 26;6(3). Epub 2019 Aug 26.

Faculty of Chemistry, Brno University of Technology, Purkynova 118, 612 00 Brno, Czech Republic.

The terpolymer of 3-hydroxybutyrate (3HB), 3-hydroxyvalerate (3HV), and 4-hydroxybutyrate (4HB) was produced employing sp. DSM 19379. Growth in the presence of γ-butyrolactone, ε-caprolactone, 1,4-butanediol, and 1,6-hexanediol resulted in the synthesis of a polymer consisting of 3HB and 4HB monomers. Single and two-stage terpolymer production strategies were utilized to incorporate the 3HV subunit into the polymer structure. At the single-stage cultivation mode, γ-butyrolactone or 1,4-butanediol served as the primary substrate and propionic and valeric acid as the precursor of 3HV. In the two-stage production, glycerol was used in the growth phase, and precursors for the formation of the terpolymer in combination with the nitrogen limitation in the medium were used in the second phase. The aim of this work was to maximize the Polyhydroxyalkanoates (PHA) yields with a high proportion of 3HV and 4HB using different culture strategies. The obtained polymers contained 0-29 mol% of 3HV and 16-32 mol% of 4HB. Selected polymers were subjected to a material properties analysis such as differential scanning calorimetry (DSC), thermogravimetry, and size exclusion chromatography coupled with multi angle light scattering (SEC-MALS) for determination of the molecular weight. The number of polymers in the biomass, as well as the monomer composition of the polymer were determined by gas chromatography.
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http://dx.doi.org/10.3390/bioengineering6030074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783845PMC
August 2019

A simple technique for assessing the cuticular diffusion of humic acid biostimulants.

Plant Methods 2019 31;15:83. Epub 2019 Jul 31.

1Institute of Physical and Applied Chemistry, Brno University of Technology, Faculty of Chemistry, Purkynova 464/118, 612 00 Brno, Czech Republic.

Background: Experimental determination of the extent and rate of transport of liquid humates supplied to plants is critical in testing physiological effects of such biostimulants which are often supplied as foliar sprays. Therefore, an original experimental method for the qualitative investigation and quantitative description of the penetration of humates through plant cuticles is proposed, tested, and evaluated.

Results: The proposed method involves the isolation of model plant leaf cuticles and the subsequent in vitro evaluation of cuticular humate transport. The employed novel methodology is based on a simple diffusion couple arrangement involving continuous spectrophotometric determination of the amount of penetrated humate in a hydrogel diffusion medium. leaf cuticles were isolated by chemical and enzymatic treatment and the rate of cuticular penetration of a commercial humate (lignohumate) was estimated over time in quantitative and qualitative terms. Different rates of lignohumate transport were determined for abaxial and adaxial leaf cuticles also in relation to the different cuticular extraction methods tested.

Conclusions: The proposed methodology represents a simple and cheap experimental tool for the study on the trans-cuticular penetration of humic-based biostimulants.
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http://dx.doi.org/10.1186/s13007-019-0469-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668121PMC
July 2019

Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia from a Matched Donor versus an HLA-Identical Sibling: Is the Outcome Comparable? Results from the International BFM ALL SCT 2007 Study.

Biol Blood Marrow Transplant 2019 11 15;25(11):2197-2210. Epub 2019 Jul 15.

St Anna Children's Hospital, UKKJ, MUW, Vienna, Austria.

Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL. The 4-year event-free survival (65 ± 5% vs 61 ± 4%; P = .287), overall survival (72 ± 4% versus 68 ± 4%; P = .235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; P = .658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001). Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.011DOI Listing
November 2019

How Humic Acids Affect the Rheological and Transport Properties of Hydrogels.

Molecules 2019 Apr 19;24(8). Epub 2019 Apr 19.

Materials Research Centre, Faculty of Chemistry, Brno University of Technology, Purkynova 118/464, 612 00 Brno, Czech Republic.

Humic acids are often regarded as substances with a supramolecular structure which plays an important role in Nature. Their addition into hydrogels can affect their behavior and functioning in different applications. This work is focused on the properties of widely-used hydrogel based on agarose after addition of humic acids-the protonated H-form of humic acids and humic acids with methylated carboxylic groups. Hydrogels enriched by humic acids were studied in terms of their viscoelastic and transport properties. Rotational rheometry and methods employing diffusion cells were used in order to describe the influence of humic acids on the properties and behavior of hydrogels. From the point of view of rheology the addition of humic acids mainly affected the loss modulus corresponding to the relaxation of hydrogel connected with its flow. In the case of diffusion experiments, the transport of dyes (methylene blue and rhodamine) and metal ions (copper and nickel) through the hydrogel was affected by interactions between humic acids and the diffusion probes. The time lag in the hydrogel enriched by humic acids was prolonged for copper, methylene blue and rhodamine. In contrast, the presence of humic acids in hydrogel slightly increased the mobility of nickel. The strongest influence of the methylation of humic acids on diffusion was observed for methylene blue.
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http://dx.doi.org/10.3390/molecules24081545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515218PMC
April 2019

Synergistic effect of bovine platelet lysate and various polysaccharides on the biological properties of collagen-based scaffolds for tissue engineering: Scaffold preparation, chemo-physical characterization, in vitro and ex ovo evaluation.

Mater Sci Eng C Mater Biol Appl 2019 Jul 26;100:236-246. Epub 2019 Feb 26.

CEITEC - Central European Institute of Technology, Brno University of Technology, Advanced Biomaterials, Purkynova 656/123, 612 00 Brno, Czech Republic.

Crosslinked 3D porous collagen-polysaccharide scaffolds, prepared by freeze-drying, were modified with bovine platelet lysate (BPL) and evaluated in terms of chemical, physical and biological properties. Natural antibacterial polysaccharides like chitosan, chitin/chitosan-glucan complex and calcium salt of oxidized cellulose (CaOC) incorporated in collagen scaffolds affected not only chemo-physical properties of the composite scaffolds but also improved their biological properties, especially when BPL was presented. Lipophilic BPL formed microspheres in porous scaffolds while reduced by half their swelling ratio. The resistance of collagen sponges to hydrolytic degradation in water depended strongly on chemical crosslinking varying from 60 min to more than one year. According to in-vitro tests, chemically crosslinked scaffolds exhibited a good cellular response, cell-matrix interactions, and biocompatibility of the material. The combination of collagen with natural polysaccharides confirmed a significant positive synergistic effect on cultivation of cells as determined by MTS assay and PicoGreen method, as well as on angiogenesis evaluated by ex ovo Chick Chorioallantoic Membrane (CAM) assay. Contrary, modification only by BLP of pure collagen scaffolds exhibited decreased biocompatibility in comparison to unmodified pure collagen scaffold. We propose that the newly developed crosslinked collagen sponges involving bioactive additives could be used as scaffold for growing cells in systems with low mechanical loading in tissue engineering, especially in dermis replacement, where neovascularization is a crucial parameter for successful skin regeneration.
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http://dx.doi.org/10.1016/j.msec.2019.02.092DOI Listing
July 2019

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study.

J Allergy Clin Immunol 2019 06 17;143(6):2238-2253. Epub 2019 Jan 17.

Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT).

Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics.

Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure.

Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%.

Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.
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http://dx.doi.org/10.1016/j.jaci.2018.12.1010DOI Listing
June 2019