Metabolomic Alterations Associated with Phthalate Exposures among Pregnant Women in Puerto Rico.

Although phthalate exposure has been linked with multiple adverse pregnancy outcomes, their underlying biological mechanisms are not fully understood. We examined associations between biomarkers of phthalate exposures and metabolic alterations using untargeted metabolomics in 99 pregnant women and 86 newborns [mean (SD) gestational age = 39.5 (1.5) weeks] in the PROTECT cohort. Maternal urinary phthalate metabolites were quantified using isotope dilution high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), while metabolic profiles in maternal and cord blood plasma were characterized via reversed-phase LC-MS. Multivariable linear regression was used in metabolome-wide association studies (MWAS) to identify individual metabolic features associated with elevated phthalate levels, while clustering and correlation network analyses were used to discern the interconnectedness of biologically relevant features. In the MWAS adjusted for maternal age and prepregnancy BMI, we observed significant associations between specific phthalates, namely, di(2-ethylhexyl) phthalate (DEHP) and mono(3-carboxypropyl) phthalate (MCPP), and 34 maternal plasma metabolic features. These associations predominantly included upregulation of fatty acids, amino acids, purines, or their derivatives and downregulation of ceramides and sphingomyelins. In contrast, fewer significant associations were observed with metabolic features in cord blood. Correlation network analysis highlighted the overlap of features associated with phthalates and those identified as differentiating markers for preterm birth in a previous study. Overall, our findings underscore the complex impact of phthalate exposures on maternal and fetal metabolism, highlighting metabolomics as a tool for understanding associated biological processes. Future research should focus on expanding the sample size, exploring the effects of phthalate mixtures, and validating identified metabolic features in larger, more diverse populations.

Vitamin D concentration in the blood of women with twin pregnancies and in the umbilical cord blood of newborns in relation to environmental factors.

Background: There is a huge gap in the knowledge of the body's nutrient resources in women with multiple gestations. Due to the increased demand hypothesis and taking into account common vitamin D deficits in women with singleton pregnancies, this issue should also be investigated in twin pregnancies. This study evaluated blood vitamin D concentration in women with twin pregnancies and in the umbilical cord blood of their newborns as well as analyzed environmental factors that may affect the level of this nutrient. Methods: The study included 56 women with twin pregnancies. Venous blood samples were collected from the women before delivery and umbilical cord blood at delivery to determine the total 25(OH)D concentration. The women were interviewed by a dietitian to collect data on their diet and lifestyle. Results: The average maternal 25(OH)D concentrations were 38.4 ± 11.0 ng/mL vs. 23.7 ± 6.1 ng/mL determined in the umbilical cord blood of the newborns. The concentration of 25(OH)D in the umbilical cord blood was strongly correlated with the concentration in the mother (p < 0.001). Vitamin D deficiency was found in 7% of women and 21% of newborns. Factors increasing the risk of too low 25(OH)D concentration in the mothers were age below 27 years (p = 0.002) and short duration of pregnancy (p = 0.011). In newborns, the risk factors included low maternal concentrations (p < 0.001) and delivery before 36 weeks of gestation (p = 0.008). The mean cord blood 25(OH)D levels were almost identical in both twins and amounted to 24.0 ± 6.1 ng/mL in the first-born and 23.4 ± 6.1 ng/mL in the second-born infant. Vitamin D supplementation was declared by 98% of the women, with 85% taking ≤2,000 IU vitamin D daily. Conclusion: Only a small percentage of women with twin pregnancies presented with vitamin D deficiency, which was probably related to the widespread supplementation of this nutrient. It can therefore be assumed that a dose of 2,000 IU vitamin D currently recommended for pregnant women may also be appropriate for twin gestations, although further research is required to validate this finding.

hsa-miR-582-3p in umbilical cord blood is negatively associated with maternal exposure to childhood maltreatment.

Aim: Childhood maltreatment (CM) may affect not only directly exposed individuals but also their offspring. However, the underlying biological mechanisms remain unclear. microRNAs (miRNAs) may play a regulatory role in this process. This study investigates the relationship between maternal exposure to CM and miRNA expression in maternal and perinatal tissues.Methods: We enrolled 43 pregnant women and assessed their CM exposure. We collected maternal blood, cord blood and placental tissue samples during childbirth and performed miRNA profiling using next generation sequencing.Results: Maternal CM was inversely associated with hsa-miR-582-3p levels in cord blood. Pathway analysis revealed that this miRNA regulates genes involved in intrauterine development.Conclusion: Our findings highlight the potential impact of maternal CM exposure on offspring epigenetic mechanisms.

Child maltreatment (CM) includes physical, sexual and emotional abuse, as well as physical and emotional neglect. CM not only harms those directly exposed but can also negatively impact their offspring. However, the biological reasons behind this are not well understood. To explore this further, our study investigates how CM affects the biology of pregnant women and their newborns through changes in small regulatory molecules called microRNAs (miRNAs). We recruited 43 pregnant women and assessed their exposure to CM. During childbirth, we collected blood samples from the mothers, blood from the umbilical cord and placental samples. We then analyzed the levels of miRNAs in these samples using advanced sequencing technology. We observed that more severe maternal exposure to CM was associated with lower levels of a miRNA named hsa-miR-582-3p in umbilical cord blood. This miRNA regulates genes involved in fetal development in utero and has been linked to spontaneous preterm birth. It may also influence immunologic and stress-related processes. Thus, newborns of mothers who had been exposed to CM may be more vulnerable to adverse effects on their brain development and overall health. Despite our small sample size, our study highlights the importance of addressing CM as an intergenerational concern and provides new insights into the biological mechanisms through which maternal CM can affect offspring.

The efficacy and safety of third-party umbilical blood/umbilical cord mesenchymal stem cell assisted related haploid hematopoietic stem cell transplantation in pediatric patients with acute leukemia: an observational study.

Background: There is limited data on third-party umbilical cord blood (UCB) or mesenchymal stem cell (MSC) transplantation-assisted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in pediatric patients. Objective: To evaluate the efficacy and safety of UCB and MSC transplantation-assisted haplo-HSCT in pediatric patients with acute leukemia (AL). Design: Observational study. Methods: Clinical data of 152 children with AL undergoing haplo-HSCT at the Children's Hospital of Soochow University between January 2020 and June 2022 were collected. The patients were divided into the haplo-HSCT + UCB group (n = 76), haplo-HSCT + MSC group (n = 31), and haplo-HSCT group (n = 45). Hematopoietic reconstruction time, complications within 30 days after transplantation, and survival and recurrence at 3 years after transplantation were compared among the groups. Results: Multivariate analysis revealed that haplo-HSCT with MSC and human leukocyte antigen (HLA) matching ⩾6/10 were independent factors reducing engraftment syndrome (ES) incidence. There were no significant differences among the groups in the hematopoietic reconstruction time or incidence of complications within 30 days after transplantation (p > 0.05). Overall survival, relapse-free survival, cumulative incidence of relapse, cumulative incidence of hematological relapse, and 3-year transplant-related mortality were not significantly different (p > 0.05). The incidence of adverse reactions in the haplo-HSCT + UCB group was 97.3% within 4 h after UCB infusion, with a particularly high occurrence rate of 94.7% for hypertension. No transfusion-related adverse reactions occurred after the transfusion of umbilical cord MSC in the haplo-HSCT + MSC group. Conclusion: MSC-assisted haplo-HSCT can reduce ES incidence after transplantation in pediatric patients with AL. UCB infusion is associated with a high incidence of reversible hypertension. However, no adverse reactions were observed in umbilical cord MSC transfusion.

Prenatal black carbon exposure and DNA methylation in umbilical cord blood.

BACKGROUND/OBJECTIVES: Prenatal exposure to ambient air pollution is associated with adverse cardiometabolic outcomes in childhood. We previously observed that prenatal black carbon (BC) was inversely associated with adiponectin, a hormone secreted by adipocytes, in early childhood. Changes to DNA methylation have been proposed as a potential mediator linking in utero exposures to lasting health impacts. METHODS: Among 532 mother-child pairs enrolled in the Colorado-based Healthy Start study, we performed an epigenome-wide association study of the relationship between prenatal exposure to a component of air pollution, BC, and DNA methylation in cord blood. Average pregnancy ambient BC was estimated at the mother's residence using a spatiotemporal prediction model. DNA methylation was measured using the Illumina 450K array. We used multiple linear regression to estimate associations between prenatal ambient BC and 429,246 cysteine-phosphate-guanine sites (CpGs), adjusting for potential confounders. We identified differentially methylated regions (DMRs) using DMRff and ENmix-combp. In a subset of participants (n = 243), we investigated DNA methylation as a potential mediator of the association between prenatal ambient BC and lower adiponectin in childhood. RESULTS: We identified 44 CpGs associated with average prenatal ambient BC after correcting for multiple testing. Several genes annotated to the top CpGs had reported functions in the immune system. There were 24 DMRs identified by both DMRff and ENmix-combp. One CpG (cg01123250), located on chromosome 2 and annotated to the UNC80 gene, was found to mediate approximately 20% of the effect of prenatal BC on childhood adiponectin, though the confidence interval was wide (95% CI: 3, 84). CONCLUSIONS: Prenatal BC was associated with DNA methylation in cord blood at several sites and regions in the genome. DNA methylation may partially mediate associations between prenatal BC and childhood cardiometabolic outcomes.

Successful Cord Blood Transplantation for Myeloid/Natural Killer Precursor Acute Leukemia: A Case Report and Literature Review.

A 21-year-old man was diagnosed with myeloid/natural killer precursor leukemia (MNKPL) with bone marrow infiltration of blasts of cyCD3+, CD7+, CD33+, CD34dim, CD56+/-, HLA-DR+, cyMPO+, and TdT- immunophenotypes. Although hyper-CVAD therapy was unsuccessful, induction treatment with idarubicin and cytarabine resulted in complete remission (CR). The patient subsequently underwent cord blood transplantation with a myeloablative conditioning regimen, which resulted in durable CR and complete donor chimerism. He had been in good health without relapse for over nine months since transplantation. Timely allogeneic hematopoietic stem cell transplantation using an available donor source may be a promising treatment strategy for MNKPL.

Bulk and single-cell transcriptomics identify gene signatures of stem cell-derived NK cell donors with superior cytolytic activity.

Allogeneic natural killer (NK) cell therapies are a valuable treatment option for cancer, given their remarkable safety and favorable efficacy profile. Although the use of allogeneic donors allows for off-the-shelf and timely patient treatment, intrinsic interindividual differences put clinical efficacy at risk. The identification of donors with superior anti-tumor activity is essential to ensure the success of adoptive NK cell therapies. Here, we investigated the heterogeneity of 10 umbilical cord blood stem cell-derived NK cell batches. First, we evaluated the donors' cytotoxic potential against tumor cell lines from solid and hematological cancer indications, to distinguish a group of superior, "excellent" killers (4/10), compared with "good" killers (6/10). Next, bulk and single-cell RNA sequencing, performed at different stages of NK differentiation, revealed distinct transcriptomic features of the two groups. Excellent donors showed an enrichment in cytotoxicity pathways and a depletion of myeloid traits, linked to the presence of a larger population of effector-like NK cells early on during differentiation. Consequently, we defined a multi-factorial gene expression signature able to predict the donors' cytotoxic potential. Our study contributes to the identification of key traits of superior NK cell batches, supporting the development of efficacious NK therapeutics and the achievement of durable anti-tumor responses.

Immune Biomarkers at Birth Predict Lower Respiratory Tract Infection Risk in a Large Birth Cohort.

Lower respiratory tract infections (LRTIs) remain the leading cause of infant morbidity and mortality worldwide and affect long-term respiratory health. Identifying immunological determinants of LRTI susceptibility may help stratify disease risk and identify therapies. This study aimed to identify neonatal immunological factors predicting LRTI risk in infancy. Cord blood plasma from 191 neonates from the Boston Birth Cohort was analyzed for 28 soluble immune factors. LRTI was defined as bronchiolitis, bronchitis, or pneumonia during the first year of life. Welch's t-test demonstrated significantly higher log10 transformed concentrations of IL-17 and IFNγ in the LRTI group compared to neonates without LRTI in the first year of life (p < 0.05). Risk associations were determined using multivariate survival models. There were 29 infants with LRTIs. High cord blood levels of IFNγ (aHR = 2.35, 95% CI 1.07-5.17), TNF-ß (aHR = 2.86, 95% CI 1.27-6.47), MIP-1α (aHR = 2.82, 95% CI 1.22-6.51), and MIP-1ß (aHR = 2.34, 95% CI 1.05-5.20) were associated with a higher risk of LRTIs. RANTES was associated with a lower risk (aHR = 0.43, 95% CI 0.19-0.97). Soluble immune factors linked to antiviral immunity (IFNγ) and cytokines mediating inflammatory responses (TNF-ß), and cell homing (MIP-1α/b), at birth were associated with an increased risk of LRTIs during infancy.

Macrophage extracellular vesicle-packaged miR-23a-3p impairs maintenance and angiogenic capacity of human endothelial progenitor cells in neonatal hyperoxia-induced lung injury.

BACKGROUND: Premature infants requiring mechanical ventilation and supplemental oxygen for respiratory support are at increased risk for bronchopulmonary dysplasia (BPD), wherein inflammation have been proposed as a driver of hyperoxia-induced injuries, including persistent loss of endothelial progenitor cells (EPCs), impaired vascularization and eventual alveolar simplification in BPD lungs. However, the underlying mechanisms linking these phenomena remain poorly defined. METHODS: We used clodronate liposomes to deplete macrophages in a mouse model of neonatal hyperoxia-induced lung injury to evaluate if EPC loss in BPD lungs could be an effect of macrophage infiltration. We further generated in vitro culture systems initiated with cord blood (CB)-derived CD34+ EPCs and neonatal macrophages either polarized from CB-derived monocytes or isolated from tracheal aspirates of human preterm infants requiring mechanical ventilation and oxygen supplementation, to identify EV-transmitted molecular mechanism that is critical for inhibitory actions of hyperoxic macrophages on EPCs. RESULTS: Initial experiments using mouse model identified the crucial role of macrophage infiltration in eliciting significant reduction of c-Kit+ EPCs in BPD lungs. Further examination of this concept in human system, we found that hyperoxia-exposed neonatal macrophages hamper human CD34+ EPC maintenance and impair endothelial function in the differentiated progeny via the EV transmission of miR-23a-3p. Notably, treatment with antagomiR-23a-3p to silence miR-23a-3p in vivo enhances c-Kit+ EPC maintenance, and increases capillary density, and consequently mitigates simplified alveolarization in BPD lungs. CONCLUSION: Our findings highlight the importance of pulmonary intercellular communication in the pathophysiology of BPD, by identifying a linkage through vesicle transfer of miR-23a-3p from hyperoxic macrophages to EPCs, and thus demonstrating potential for novel therapeutic target in BPD.

Awareness and Attitude of Pregnant Couple Toward Umbilical Cord Blood Banking in Telangana: A Cross-sectional Study.

Banking of umbilical cord blood (UCB) is performed to collect and store umbilical cord stem cells. Both public and private cord blood banks have been established around the world. The study aimed to determine the level of awareness of UCB banking among pregnant couples and to assess the attitude of the couples toward UCB banking. We also tried to explore the factors influencing the UCB banking donation and the couple's expectations of UCB banking in the future. A prevalidated questionnaire on UCB banking was administered, and the interview was conducted among the same pregnant couples (both husband and wife) attending the obstetrics and gynecology (OBG) outpatient department (OPD). Only 28% (N = 121) of the participants had heard of UCB banking, and only 12% had correct knowledge of UCB banking. Only 4.9% of participants had heard of public or private UCB banks. Only one couple of 121 has stored UCB in their previous pregnancy, and about 36% of couples were willing to store their newborn's UCB in the present pregnancy. Poor understanding continues to be a significant barrier to reaping the benefits of UCB and preservation. Obstetricians and pediatricians should take a more active role in educating patients about the benefits and drawbacks of UCB banking.

Reduced B cell frequencies in cord blood of HIV-exposed uninfected infants: an immunological and transcriptomic analysis.

Introduction: In the course of immune development, HIV-exposed uninfected (HEU) infants exhibit abnormal immune function and increased infectious morbidity compared to HIV-unexposed uninfected (HUU) infants. Yet the specific functional phenotypes and regulatory mechanisms associated with in-utero HIV and/or ART exposure remain largely obscure. Methods: We utilized flow cytometry and RNA-seq technologies to conduct the immunological and transcriptomic profiling in cord blood from 9 HEU mother-infant pairs and 24 HUU pairs. On top of that, we compared the cord blood dataset with the maternal venous blood dataset to characterize unique effects induced by in-utero HIV and/or ART exposure. Results: Flow cytometry immunophenotyping revealed that the level of B lymphocyte subsets was significantly decreased in HEU cord blood as compared to HUU (P < 0.001). Expression profiling-based cell abundance assessment, includes CIBERSORT and ssGSEA algorithm, showed a significantly reduced abundance of naive B cells in HEU cord blood (both P < 0.05), supporting the altered composition of B lymphocyte subsets in HEU. Functional enrichment analysis demonstrated suppressed innate immune responses and impaired immune regulatory function of B cells in HEU cord blood. Furthermore, through differential expression analysis, co-expression network analysis using WGCNA, and feature selection analysis using LASSO, we identified a 4-gene signature associated with HEU status. This signature effectively assesses B cell levels in cord blood, enabling discrimination between HEU and HUU infants. Discussion: Our study provides the first comprehensive immunological and transcriptomic characterization of HEU cord blood. Additionally, we establish a 4-gene-based classifier that holds potential for predict immunological abnormalities in HEU infants.

Umbilical cord blood-derived exosomes attenuate dopaminergic neuron damage of Parkinson's disease mouse model.

BACKGROUND: Umbilical cord blood (UCB) is a rich source of multifunctional stem cells characterized by low immunogenicity. Recent research in the fields of aging and regenerative medicine has revealed the potential of human umbilical cord blood-derived exosomes (UCB-Exos) in promoting wound healing, anti-aging, and regeneration. However, their role in neurodegenerative diseases, specifically Parkinson's disease (PD), remains unexplored. This study investigates the potential therapeutic effects and underlying mechanisms of UCB-Exos on PD. METHODS: Large extracellular vesicles (LEv), Exos, and soluble fractions (SF) of human UCB plasma were extracted to investigate their effects on motor dysfunction of the MPTP-induced PD mouse model and identify the key components that improve PD symptoms. UCB-Exos were administered by the caudal vein to prevent or treat the PD mouse model. The motor function and pathological markers were detected. Differentially expressed gene and KEGG enrichment pathways were screened by transcriptome sequence. MN9D and SH-SY5Y cells were cultured and evaluated for cell viability, oxidative stress, cell cycle, and aging-related indexes by qRT-PCR, western blot, immunofluorescence, and flow cytometry. The protein expression level of the MAPK p38 and ERK1/2 signaling pathway was detected by western blot. RESULTS: We observed that LEv, Exos, and SF all exhibited potential in ameliorating motor dysfunction in MPTP-induced PD model mice, with UCB-Exos demonstrating the most significant effect. UCB-Exos showed comparable efficacy in preventing and treating motor dysfunction, cognitive decline, and substantia nigra pathological damage in PD mice. Further investigations revealed that UCB-Exos could potentially alleviate oxidative damage, aging and degeneration, and energy metabolism disorders in neurons. Transcriptome sequencing results corroborated that genes differentially expressed due to UCB-Exos were primarily enriched in the neuroactive ligand-receptor interaction, Dopaminergic synapse, and MAPK signaling pathway. We also observed that UCB-Exos significantly inhibited the hyperphosphorylation of the MAPK p38 and ERK1/2 signaling pathways both in vitro and in vivo. CONCLUSIONS: Our study provides a comprehensive evaluation of UCB-Exos on the neuroprotective effects and suggests that inhibition of hyperphosphorylation of MAPK p38 and ERK 1/2 signaling pathways by regulating transcription levels of HspB1 and Ppef2 may be the key mechanism for UCB-Exos to improve PD-related pathological features.

Investigation of Mother-to-Child Transmission of Hepatitis B in Yinchuan, China: Cross-Sectional Survey Study.

BACKGROUND: Hepatitis B poses a significant global public health challenge, with mother-to-child transmission (MTCT) being the primary method of hepatitis B virus (HBV) transmission. The prevalence of HBV infection in China is the highest in Asia, and it carries the greatest burden globally. OBJECTIVE: This study aims to critically evaluate the existing local strategies for preventing MTCT and the proposed potential enhancements by analyzing the prevalence of hepatitis B among pregnant women and their neonates in Yinchuan. METHODS: From January 2017 to December 2021, 37,557 prenatal screening records were collected. Among them, 947 pregnant women who tested positive for hepatitis B surface antigen (HBsAg) near delivery and their 960 neonates were included in an HBV-exposed group, while 29 pregnant women who tested negative and their 30 neonates were included in an HBV-nonexposed group. HBV markers in maternal peripheral blood and neonatal cord blood were analyzed using the least absolute shrinkage and selection operator (LASSO) regression, logistic regression, chi-square test, t-test, and U-test. Additionally, to further evaluate the diagnostic value of HBsAg positivity in cord blood, we conducted an additional follow-up study on 103 infants who tested positive for HBsAg in their cord blood. RESULTS: The prevalence of HBV among pregnant women was 2.5% (947/37,557), with a declining trend every year (χ²4=19.7; P=.001). From 2018 to 2020, only 33.0% (35/106) of eligible pregnant women received antiviral medication treatment. Using LASSO regression to screen risk factors correlated with HBsAg positivity in cord blood (when log [λ] reached a minimum value of -5.02), 5 variables with nonzero coefficients were selected, including maternal hepatitis B e-antigen (HBeAg) status, maternal hepatitis B core antibody (HBcAb) status, maternal HBV DNA load, delivery method, and neonatal birth weight. Through univariate and multivariate logistic regression, delivery by cesarean section (adjusted odds ratio [aOR] 0.52, 95% CI 0.31-0.87), maternal HBeAg positivity (aOR 2.05, 95% CI 1.27-3.33), low maternal viral load (aOR 2.69, 95% CI 1.33-5.46), and high maternal viral load (aOR 2.69, 95% CI 1.32-5.51) were found to be strongly associated with cord blood HBsAg positivity. In the additional follow-up study, 61 infants successfully completed the follow-up, and only 2 were found to be infected with HBV. The mothers of both these infants had detectable HBV DNA levels and should have received standard antiviral therapy. The results of the hepatitis B surface antibody (HBsAb) positivity rate and titer test indicated a gradual decline in the immunity of vaccinated infants as the interval after vaccination increased. CONCLUSIONS: The clinical relevance of HBV marker detection in cord blood is restricted within the current prevention measures for MTCT. There is an emphasis on the significance of public education regarding hepatitis B and the reinforcement of postnatal follow-up for the prevention of MTCT.

Extensive immunophenotypic sub-population analysis of StemRegenin1 expanded haematopoietic stem/progenitor cells.

BACKGROUND: Ex vivo haematopoietic stem/progenitor cell (HSPCs) expansion constitutes an important area of research, and has the potential to improve access to umbilical cord blood (UCB) as a source of stem cells for haematopoietic stem cell transplantation (HSCT). The ability to improve stem cell dose and thereby reduce delayed engraftment times, which has plagued the use of UCB as a stem cell source since inception, is a recognised advantage. The extent to which cluster of differentiation (CD)34 sub-populations are affected by expansion with StemRegenin1 (SR1), and whether a particular subtype may account for better engraftment than others, is currently unknown. The purpose of this study was to determine the impact of SR1-induced HSPC expansion on CD34+ immunophenotypic subsets and gene expression profiles. METHODS: UCB-derived CD34+ HSPCs were characterised before (D0) and after expansion (D7) with SR1 using an extensive immunophenotypic panel. In addition, gene expression was assessed and differentially expressed genes were categorised into biological processes. RESULTS: A dose-dependent increase in the number of CD34+ HSPCs was observed with SR1 treatment, and unbiased and extensive HSPC immunophenotyping proved to be a powerful tool in identifying unique sub-populations within the HSPC repertoire. In this regard, we found that SR1 promotes the emergence of HSPC subsets which may aid engraftment post expansion. In addition, we observed that SR1 has a minimal effect on the transcriptome of 7-day expanded CD34+ HSPCs when compared to cells expanded without SR1, with only two genes being downregulated in the former. CONCLUSION: This study revealed that SR1 selects for potentially novel immunophenotypic HSPC subsets post expansion and has a minimal effect on the transcriptome of 7-day expanded HSPCs when compared to vehicle controls. Whether these distinct immunophenotypic sub-populations possess greater engraftment capacity remains to be tested in animal models.

Using autologous umbilical cord blood and placental cells for hypoxic-ischemic encephalopathy: an exploratory safety and feasibility study. / Células autólogas de sangre de cordón umbilical y placenta para la encefalopatía hipóxico isquémica: estudio exploratorio de seguridad y factibilidad.

Introduction. Hypoxic-ischemic encephalopathy (HIE) caused by lack of oxygen and perfusion to the brain can lead to acute neurological damage in newborns. Therapeutic hypothermia (TH) is the most effective and safest treatment. However, mortality remains high with numerous long-term sequelae. Cellular therapies, particularly umbilical cord blood (UCB), are being studied as alternative therapies. The aim of this study is to assess the feasibility and safety of combining autologous cord blood cell infusion with moderate hypothermia. Population and methods. Twelve infants of 36 weeks gestational age or older, diagnosed with moderate or severe HIE and with umbilical cord blood (UCB) collected were included. UCB was volume-reduced, and up to four doses were obtained. These doses were infused within the first 72 postnatal hours. Time to the first infusion and possible adverse reactions to the infusion were evaluated. Results. Between 2014 and 2019, 12 infants were included in the protocol (TH + UCB), 9 with a diagnosis of moderate HIE and 3 with severe HIE. In all cases, at least one dose of UCB was obtained for infusion. In all cases, the first dose was infused within 24 hours in every case, and no adverse reactions attributable to the infusion were observed. Conclusions. The collection, processing, and infusion of fresh autologous umbilical cord blood for use in newborns with HIE are feasible and safe under our conditions.

Introducción. La encefalopatía hipóxico-isquémica (EHI) causada por la falta de oxígeno y/o perfusión al cerebro puede provocar daño neurológico agudo en el recién nacido. La hipotermia terapéutica (HT) es el tratamiento más eficaz y seguro. Sin embargo, la mortalidad sigue siendo alta y con numerosas secuelas a largo plazo. Las terapias celulares y, en particular, la sangre de cordón umbilical (SCU) se estudian como terapias alternativas. El objetivo de este trabajo es evaluar la factibilidad y seguridad de la infusión de células autólogas de la sangre de cordón junto con la hipotermia moderada. Población y métodos. Se incorporaron 12 bebés de 36 semanas o más de gestación con diagnóstico de EHI moderada o grave y que contaban con colecta de SCU. La SCU se redujo en volumen y se obtuvieron hasta 4 dosis, que fueron infundidas en las primeras 72 horas posnatales. Se evaluó el tiempo a la primera infusión y posibles reacciones adversas a la infusión. Resultados. Entre los años 2014 y 2019, 12 bebés fueron incluidos en el protocolo (HT + SCU), 9 con diagnóstico de EHI moderada y 3 con EHI grave. En todos los casos, se obtuvo al menos 1 dosis de SCU para infundir. En todos los casos, fue posible infundir la primera dosis antes de las 24 horas y no hubo reacciones adversas atribuibles a la infusión. Conclusiones. La colecta, preparación e infusión de sangre de cordón umbilical autóloga fresca para su uso en recién nacidos con EHI es factible y segura en nuestras condiciones.

Proteomics reveals dynamic metabolic changes in human hematopoietic stem progenitor cells from fetal to adulthood.

BACKGROUND: Hematopoietic stem progenitor cells (HSPCs) undergo phenotypical and functional changes during their emergence and development. Although the molecular programs governing the development of human hematopoietic stem cells (HSCs) have been investigated broadly, the relationships between dynamic metabolic alterations and their functions remain poorly characterized. METHODS: In this study, we comprehensively described the proteomics of HSPCs in the human fetal liver (FL), umbilical cord blood (UCB), and adult bone marrow (aBM). The metabolic state of human HSPCs was assessed via a Seahorse assay, RT‒PCR, and flow cytometry-based metabolic-related analysis. To investigate whether perturbing glutathione metabolism affects reactive oxygen species (ROS) production, the metabolic state, and the expansion of human HSPCs, HSPCs were treated with buthionine sulfoximine (BSO), an inhibitor of glutathione synthetase, and N-acetyl-L-cysteine (NAC). RESULTS: We investigated the metabolomic landscape of human HSPCs from the fetal, perinatal, and adult developmental stages by in-depth quantitative proteomics and predicted a metabolic switch from the oxidative state to the glycolytic state during human HSPC development. Seahorse assays, mitochondrial activity, ROS level, glucose uptake, and protein synthesis rate analysis supported our findings. In addition, immune-related pathways and antigen presentation were upregulated in UCB or aBM HSPCs, indicating their functional maturation upon development. Glutathione-related metabolic perturbations resulted in distinct responses in human HSPCs and progenitors. Furthermore, the molecular and immunophenotypic differences between human HSPCs at different developmental stages were revealed at the protein level for the first time. CONCLUSION: The metabolic landscape of human HSPCs at three developmental stages (FL, UCB, and aBM), combined with proteomics and functional validations, substantially extends our understanding of HSC metabolic regulation. These findings provide valuable resources for understanding human HSC function and development during fetal and adult life.

Levels of C-Reactive Protein and Body Temperature Elevation During Neutropenia Predict Engraftment and Non-Relapse Mortality for Unrelated Single-Unit Cord Blood Transplantation in Adults.

Cord blood transplantation (CBT) presents unique challenges related to inflammation during neutropenia, such as mucosal damage, infections, and the potential development of pre-engraftment syndrome or pre-engraftment immune reaction. These factors can contribute to significant inflammation and infection shortly after CBT. However, the effect of severe inflammation during neutropenia, specifically elevated C-reactive protein (CRP) level and body temperature, on post-transplant outcomes after CBT remains unclear. This retrospective study aimed to investigate the association between maximum CRP level, maximum body temperature during neutropenia, and post-transplantation outcomes in adult patients undergoing single-unit CBT. We retrospectively evaluated the impact of maximum CRP level and maximum body temperature during neutropenia on post-transplantation outcomes in adults who underwent single-unit unrelated CBT between 1998 and 2023 at our institution. A total of 336 adult patients were included in this study. The median maximum CRP level before neutrophil recovery was 7.75 mg/dL (interquartile range [IQR], 4.70 to 12.05 mg/dL) at a median of 14 d (IQR, 8 to 16 d). The median maximum body temperature before neutrophil recovery was 39.5°C (IQR, 39.0 to 40.0°C) at a median of 15 d (IQR, 12 to 17 d). In the multivariate analysis, a maximum CRP level≥20 mg/dL was significantly associated with lower neutrophil recovery (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.23 to 0.59; P < .001), lower platelet recovery (HR, 0.28; 95% CI, 0.16 to 0.48; P < .001), and a higher incidence of veno-occlusive disease/sinusoidal obstruction syndrome (HR, 16.42; 95% CI, 4.11 to 65.54; P < .001), which resulted in higher non-relapse mortality (NRM) (HR, 5.16; 95% CI, 2.62 to 10.15; P < .001) and worse overall survival (HR, 2.81; 95% CI, 1.66 to 4.78; P < .001). Similarly, a maximum body temperature≥40.5°C was significantly associated with lower neutrophil recovery (HR, 0.51; 95% CI, 0.33 to 0.79; P = .002), lower platelet recovery (HR, 0.55; 95% CI, 0.38 to 0.79; P = .001), higher incidence of grades III to IV acute GVHD (HR, 2.93; 95% CI, 1.24 to 6.88; P = .013), and extensive chronic GVHD (HR, 2.47; 95% CI, 1.22 to 4.97; P = .011), which resulted in higher NRM (HR, 3.43; 95% CI, 1.53 to 7.67; P = .002). Maximum CRP level and maximum body temperature during neutropenia were significantly associated with lower hematopoietic recovery and higher NRM following single-unit CBT in adults. Further studies are warranted to explore early intervention strategies aimed at preventing severe inflammation and improving post-transplant outcomes in single-unit CBT.

ASTCT Consensus Recommendations on Testing and Treatment of Patients with Donor-specific Anti-HLA Antibodies.

Donor-specific anti-HLA antibodies (DSA) are an important cause of engraftment failure and may negatively impact survival outcomes of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) using an HLA-mismatched allograft. The incidence of DSA varies across studies, depending on individual factors, detection or identification methods and thresholds considered clinically relevant. Although DSA testing by multiplex bead arrays remains semiquantitative, it has been widely adopted as a standard test in most transplant centers. Additional testing to determine risk of allograft rejection may include assays with HLA antigens in natural conformation, such as flow cytometric crossmatch, and/or antibody binding assays, such as C1q testing. Patients with low level of DSA (<2,000 mean fluorescence intensity; MFI) may not require treatment, while others with very high level of DSA (>20,000 MFI) may be at very high-risk for engraftment failure despite current therapies. By contrast, in patients with moderate or high level of DSA, desensitization therapy can successfully mitigate DSA levels and improve donor cell engraftment rate, with comparable outcomes to patients without DSA. Treatment is largely empirical and multimodal, involving the removal, neutralization, and blocking of antibodies, as well as inhibition of antibody production to prevent activation of the complement cascade. Desensitization protocols are based on accumulated multicenter experience, while prospective multicenter studies remain lacking. Most patients require a full intensity protocol that includes plasma exchange, while protocols relying only on rituximab and intravenous immunoglobulin may be sufficient for patients with lower DSA levels and negative C1q and/or flow cytometric crossmatch. Monitoring DSA levels before and after HSCT could guide preemptive treatment when high levels persist after stem cell infusion. This paper aims to standardize current evidence-based practice and formulate future directions to improve upon current knowledge and advance treatment for this relatively rare, but potentially serious complication in allogeneic HSCT recipients.