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The COVID-19 pandemic has resulted in unprecedented plastic pollution from single-used personal protective equipment (PPE), especially face masks, in coastal and marine environments. The secondary pollutants, microplastics from face masks (mask MP), rise concern about their detrimental effects on marine organisms, terrestrial organisms and even human. Using a mouse model, oral exposure to mask MP at two doses, 0.1 and 1 mg MP/day for 21 days, caused no change in animal locomotion, total weight, or sperm counts, but caused damage to sperm motility with increased curvilinear velocity (VCL). The high-dose mask MP exposure caused a significant decrease in linearity (LIN) of sperm motility. Further testicular transcriptomic analysis revealed perturbed pathways related to spermatogenesis, oxidative stress, inflammation, metabolism and energy production. Collectively, our findings substantiate that microplastics from face masks yield adverse effects on mammalian reproductive capacity, highlighting the need for improved plastic waste management and development of environmentally friendly materials. [Display omitted] • Face mask microplastics of mixed sizes (mask MP) were yielded by cryosection. • Mask MP oral exposure damaged sperm motility. • Sperm swimming in a more circular direction in mask MP groups. • Disturbance of spermatogenesis, oxidative stress, immune and metabolism in testis. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for many pediatric diseases. Cellular immunotherapy, such as the use of chimeric antigen receptor T cells, has emerged recently as a highly effective modality to treat refractory lymphoid malignancies. Although HSCT and cellular immunotherapy are now considered essential parts of the current therapeutic armamentarium, both are associated with a wide range of acute complications, many of which are unique to these treatment modalities. These acute complications are seen not only in hospitalized patients but also in patients in the ambulatory setting, including the emergency department. Emergency care providers will need to be able to recognize these complications and provide appropriate initial assessment and management. In this review, we describe the acute complications associated with HSCT and cellular immunotherapy, with the emphasis on their recognition, workup, and treatment. [ABSTRACT FROM AUTHOR]

Treacher Collins syndrome (TCS, OMIM: 154500 ), an autosomal-dominant craniofacial developmental syndrome that occurs in 1 out of every 50,000 live births, is characterized by craniofacial malformation. Mutations in TCOF1 , POLR1C , or POLR1D have been identified in affected individuals. In addition to established mouse models, zebrafish models have recently emerged as an valuable method to study facial disease. In this report, we summarized the two updated articles working on the pathogenesis of the newly identified polr1c and polr1d TCS mutations (Lau et al., 2016; Noack Watt et al., 2016) and discussed the possibility of using the anti-oxidants to prevent or rescue the TCS facial phenotype (Sakai et al., 2016). Taken together, this article provides an update on the disease from basic information to pathogenesis, and further summarizes the suggested therapies from recent laboratory research. [ABSTRACT FROM AUTHOR]

Perfluorooctane sulfonate (PFOS), a hepato-toxicant and potential non-genotoxic carcinogen, was widely used in industrial and commercial products. Recent studies have revealed the ubiquitous occurrence of PFOS in the environment and in humans worldwide. The widespread contamination of PFOS in human serum raised concerns about its long-term toxic effects and its potential risks to human health. Using fatty liver mutant foie gras ( fgr −/− )/transport protein particle complex 11 (trappc11 −/− ) and PFOS-exposed wild-type zebrafish embryos as the study model, together with RNA sequencing and comparative transcriptomic analysis, we identified 499 and 1414 differential expressed genes (DEGs) in PFOS-exposed wild-type and trappc11 mutant zebrafish, respectively. Also, the gene ontology analysis on common deregulated genes was found to be associated with different metabolic processes such as the carbohydrate metabolic process, glycerol ether metabolic process, mannose biosynthetic process, de novo’ (Guanosine diphosphate) GDP- l -fucose biosynthetic process, GDP-mannose metabolic process and galactose metabolic process. Ingenuity Pathway Analysis further highlighted that these deregulated gene clusters are closely related to hepatitis, inflammation, fibrosis and cirrhosis of liver cells, suggesting that PFOS can cause liver pathogenesis and non-alcoholic fatty liver disease in zebrafish. The transcriptomic alterations revealed may serve as biomarkers for the hepatotoxic effect of PFOS. [ABSTRACT FROM AUTHOR]

Abstract: Background: Osmotic stress transcription factor 1/transforming growth factor-β-stimulated clone 22 domain 3 (Ostf1/Tsc22d3) is a transcription factor that plays an osmoregulatory role in euryhaline fishes. Its mRNA and protein levels are up-regulated under hyperosmotic stress. However, its osmoregulatory and developmental functions have not been studied in any stenohaline freshwater fishes. Zebrafish is an excellent model to perform such study to unfold the functional role of Tsc22d3. Methods: We identified the zebrafish Tsc22d3 and performed knockdown studies using morpholino antisense oligonucleotide (MO). Results: Zebrafish Tsc22d3 did not response to hypertonic stress and ts22d3 knockdown or overexpression by injecting MO or capped RNA did not change the transcriptional levels of any of the known ionocyte markers. To reveal the unknown function of zebrafish Tsc22d3, we performed several in situ molecular marker studies on tsc22d3 morphants and found that Tsc22d3 plays multi-functional roles in dorsoventral (DV) patterning, segmentation, and brain development. We then aimed to identify the mechanism of Tsc22d3 in the earliest stages of DV patterning. Our results demonstrated that tsc22d3 is a ventralizing gene that can stimulate the transcription of bone morphogenetic protein 4 (bmp4) and, thus, has a positive effect on the Bmp signaling pathway. Furthermore, we showed that Tsc22d3 interacts with deubiquitylating enzymes, ubiquitin-specific protease 15 (Usp15) and ovarian tumor domain containing protein 4 (Otud4). In addition, the interruption of Bmp4 signaling by double knockdown of usp15 and otud4 reduced the ventralized effects in tsc22d3-overexpressing embryos. Conclusions: This is the first study to identify new developmental functions of Tsc22d3 in zebrafish. General significance: Zebrafish tsc22d3 is a ventralizing gene and plays a role in early embryogenesis. [Copyright &y& Elsevier]

Abstract: Eukaryotic cells undergo rapid regulatory processes to maintain cellular homeostasis upon osmotic stress. In fishes, gill epithelial cells play main roles in these processes. Although osmoregulatory functions of fish gills have been well studied, little is known about the underlying mechanisms, particularly the hypertonic-induced signalling pathways during osmotic stress. This study reports for the first time on the osmo-sensing signal cascade that related to the medaka osmotic stress transcription factor 1 (Ostf1), a hypertonic induced immediate early gene, under hypertonic stress. Quantitative real-time PCR showed the rapid increase of Ostf1 in gill after transfer of medaka from fresh water to 50% seawater; particularly Ostf1b whose mRNA expression increased to 4 folds at 0.5h and reached to 10 folds at 6h after the transfer. The in vivo knockdown of Ostf1b profoundly inhibited SEK and JNK phosphorylation, but not p38 and ERK phosphorylation in the medaka gill tissue. To further investigate the possible role of Ostf1b in the JNK pathway, Ostf1b was ectopically expressed in HEK293 cells. Results indicated that Ostf1b is a downstream target of SEK and JNK and exerts a positive feedback loop on the JNK signalling pathway via activation of GCK and/or MLK3 proteins. Additionally, MAPK inhibitors experiments suggested that activation of the JNK pathway by hypertonicity is involved in the maintenance of Ostf1b stability, which in turn provides continuous stimulation of GCK for JNK phosphorylation. Lastly, changes in transcription levels of different water/ion transporters were found in knockdown or ecoptic over-expression of Ostf1b in medaka gills and human embryonic kidney cells, suggesting the role of Ostf1b in modulation of critical water channel/ion transporters during osmotic stress. [Copyright &y& Elsevier]

The occurrence and spatial distribution of bisphenol A (BPA) and analogues bisphenol B (BPB), bisphenol F (BPF) and bisphenol S (BPS) were investigated in microplastic on 11 beaches in Hong Kong. At 10 sites, BPA was the only detected chemical with concentrations ranged from 82.4–989 ng g−1 microplastic. BPA, BPB and BPS co-occurred at only one site, where it is located close proximity to the outfall of a sewage treatment plant. There was no significant spatial difference of BPA concentrations in microplastic when all the sites were considered, indicating that some remote and presumably cleaner beaches have been contaminated. PE, PP and PS (represented >90% of total polymers) were the most dominated polymers, but there was no correlation between polymer types and BPA concentrations. No evidence was found that the BPA and its analogues accumulate on microplastic since the concentrations were comparable to those found in the sediment. • BPA was present in all microplastic samples collected on 11 Hong Kong beaches. • BPB and BPS were only present at one site near a sewage treatment plant. • No spatial difference was found, indicating potential impact at remote sites. • No correlation was found between polymer types and BPA concentrations. [ABSTRACT FROM AUTHOR]

Glaucoma is one of the leading causes of visual impairment and blindness worldwide, and is characterized by the progressive damage of retinal ganglion cells (RGCs) and the atrophy of the optic nerve head (ONH). The exact cause of RGC loss and optic nerve damage in glaucoma is not fully understood. The high energy demands of these cells imply a higher sensitivity to mitochondrial defects. Moreover, it has been postulated that the optic nerve is vulnerable towards damage from oxidative stress and mitochondrial dysfunction. To investigate this further, we conducted a pooled analysis of mitochondrial variants related to energy production, specifically focusing on oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation (FAO). Our findings revealed that patients carrying non-synonymous (NS) mitochondrial DNA (mtDNA) variants within the OXPHOS complexes had an almost two-fold increased risk of developing glaucoma. Regarding FAO, our results demonstrated that longer-chain acylcarnitines (AC) tended to decrease, while shorter-chain AC tended to increase in patients with glaucoma. Furthermore, we observed that the knocking down cpt1a (a key rate-limiting enzyme involved in FAO) in zebrafish induced a degenerative process in the optic nerve and RGC, which resembled the characteristics observed in glaucoma. In conclusion, our study provides evidence that genes encoding mitochondrial proteins involved in energy metabolisms, such as OXPHOS and FAO, are associated with glaucoma. These findings contribute to a better understanding of the molecular mechanisms underlying glaucoma pathogenesis and may offer potential targets for therapeutic interventions in the future. [ABSTRACT FROM AUTHOR]

• Use of zebrafish model for environmental studies. • Application of transgenic technology for environmental toxicity researches. • Application of integrated omics to understand the toxic mechanism. • Use of zebrafish model for transgenerational studies. The production of large amounts of synthetic industrial and biomedical compounds, together with environmental pollutants, poses a risk to our ecosystem and induces negative effects on the health of wildlife and human beings. With the emergence of the global problem of chemical contamination, the adverse biological effects of these chemicals are gaining attention among the scientific communities, industry, governments, and the public. Among these chemicals, endocrine disrupting chemicals (EDCs) are regarded as one of the major global issues that potentially affecting our health. There is an urgent need of understanding the potential hazards of such chemicals. Zebrafish have been widely used in the aquatic toxicology. In this review, we first discuss the strategy of transgenic lines that used in the toxicological studies, followed by summarizing the current omics approaches (transcriptomics, proteomics, metabolomics, and epigenomics) on toxicities of EDCs in this model. We will also discuss the possible transgenerational effects in zebrafish and future prospective of the integrated omics approaches with customized transgenic organism. To conclude, we summarize the current findings in the field, and provide our opinions on future environmental toxicity research in the zebrafish model. [ABSTRACT FROM AUTHOR]

Cleft lip (CL) is a common congenital anomaly that can be syndromic or non-syndromic. It can be triggered by the mutation of gene or environmental factors. The incidence of CL is about 1 out of 700 live births. Facial development is a complex process, and there is no existing therapy to prevent the disease development. One of the characteristics in this facial malformation is the increased presence of reactive oxygen species (ROS). In this study, we hypothesize that the antioxidant glutathione (GSH) could help to attenuate the oxidative stress in this disease. Bioinformatics network pharmacology was applied to determine pharmacological targets and molecular mechanisms of GSH treatment for CL. Moreover, RNA-sequencing of the POLR1C knockdown osteoblast CL model was applied to validate the in silico data of using GSH in CL. Twenty-two core targets of GSH and CL were identified via various bioinformatics tools. The GO and KEGG analysis indicated that GSH could modulate two major families (matrix metalloproteinase and integrins), which are related to extracellular matrix modification and composition for facial development in CL. The findings from POLR1C knockdown model further supported the rescue response of GSH in CL. The study uncovered the possible pharmacological mechanism of GSH for treating CL. The data helps research group to focus on the specific pathways for understanding the biological action of GSH for treating the CL in the future. Image 1 • Candidate targets and mechanisms of the GSH against CL were identified. • The induction of ROS level in the polr1c knockdown CL osteoblast model. • Use of GSH attenuate oxidative stress in CL osteoblast model. • Use of GSH may help in reducing the severity of CL and the risk of CL occurrence. [ABSTRACT FROM AUTHOR]

Introduction Graft versus host disease [GVHD] remains the major factor underlying transplant induced morbidity and mortality among recipients of allogeneic stem cell transplant [allo-SCT]. Mycophenolate mofetil [MMF] plus calcineurin inhibitor [CNI] combination is mostly used in reduced intensity [RI] and nonmyeloablative conditioning [NMAC] whereas methotrexate and CNI combination is preferred in myeloablative conditioning [MAC]. We present single institution outcomes in patients undergoing allo-SCT with MMF and CNI as the only combination for GVHD prophylaxis. Methods Data from all adult patients who underwent allo-SCT at our institution from 2007 to 2016 was collected from our Center for Blood and Marrow Transplant Research [CIBMTR] portal. Results Total 141 patients were included with the median age of 50 years. Most patients were female [52%] and white [85%]. Disease characteristics included AML 56.7%, ALL 14.2%, CML 7.7%, MDS/MPD 7.7%, HL/NHL 6.4% and others 7%. MAC was used in 75.2% whereas NMAC/RI conditioning was used in 24.8% of the patients. Peripheral blood was the predominant source of stem cell graft [81%]. Donor status included 30.5% HLA matched related, 63.8% HLA mismatched/matched unrelated and 4.9% HLA mismatch related. Incidence of acute GVHD at day 100 was 49.6% [grade I 16.5%; grade II-IV 33.1%], acute GVHD at day 365 was 59.6%, and chronic GVHD at day 365 was 48.1% [limited 13.5%; extensive 34.6%]. 1-year overall survival was at 51% [95% CI 42-59%] and significantly associated with race and conditioning regimen. Discussion Based on historical cohort, combination of methotrexate and tacrolimus is associated with acute graft versus host disease in 89% [grade I 11%; grade II-IV 78%], chronic graft versus host disease in 94% [limited 32%; extensive 65%] and 1-year overall survival of 47%. Hence our institutional analysis shows that the combination of mycophenolate and tacrolimus is superior to methotrexate and tacrolimus combination for prevention of acute and chronic graft versus host disease as well as 1-year overall survival. [ABSTRACT FROM AUTHOR]

mib nn2002 , identified from an allele screen, shows early segmentation defect and severe cell death phenotypes, which are different from those of other described mib mutant alleles. We have previously reported its defects in somitogenesis and identified its origin of mutation, a large deletion in LG2. The report here is a continuous study, where we applied the bioinformatics analysis to profile the genetic background of mib nn2002 mutants. By comparing the transcriptomic data of mib nn2002 mutants with those of AB wild-type, a total of 1945 differentially expressed genes were identified, including 685 up- and 1260 down-regulated genes. The Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis and Ingenuity Pathway Analysis (IPA) identified the enriched pathways and their related biological functions. Our data further demonstrated that the defects in the somitogenesis were related to the down-regulated segmentation genes, such as foxc1a , smyhc1 , myod1 and mylpfa . [ABSTRACT FROM AUTHOR]

Benozophenone (BP) type UV filters are extensively used in the personal care products to provide protection against the harmful effects of UV radiation. BPs are one of the primary components in the UV filter family, in which benophenone-2 (BP2) is widely used as a UV filter reagent in the sunscreen. Humans used these personal care products directly on skin and the chemicals will be washed away to the water system. BP2 has been identified as one of the endocrine disruptor chemicals, which can inference the synthesis, metabolism, and action of endogenous hormones. Environmentally, it has been found to contaminate water worldwide. In this study, we aimed to unfold the possible developmental toxicology of this chemical. Zebrafish are used as the screening model to perform in situ hybridization staining to investigate the effects of BP2 on segmentation, brain regionalization, and facial formation at four developmental stages (10–12 somite, prim-5, 2 and 5 days post-fertilization). Results showed 40 μM (9.85 mg L −1 ) or above BP2 exposure in zebrafish embryos for 5 days resulted in lipid accumulation in the yolk sac and facial malformation via affecting the lipid processing and the expression of cranial neural crest cells respectively. To conclude, the study alarmed its potential developmental toxicities at high dosage exposure. [ABSTRACT FROM AUTHOR]

Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism. Metformin treatment alone resulted in significant suppression of ROS and mitochondrial respiration with increased glycolysis accompanied by modest cytotoxicity (10–25%). In contrast, 6-BT monotherapy resulted in inhibition of glucose uptake, decreased glycolysis, and decreased ATP with minimal changes in ROS and mitochondrial respiration. The combination of 6-BT with metformin resulted in significant cytotoxicity (60–70%) in monocytic AML cell lines and was associated with inhibition of FLT3-ITD activated STAT5 and reduced c-Myc and GLUT-1 expression. Therefore, although the anti-tumor and metabolic effects of metformin have been limited by the metabolic reprogramming within cells, the novel combination of 6-BT and metformin targets this bypass mechanism resulting in reduced glycolysis, STAT5 inhibition, and increased cell death. [ABSTRACT FROM AUTHOR]

Treacher Collins Syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects, including the downward slanting palpebral fissures, hypoplasia of the facial bones, and cleft palate (CP). Over 90% of patients with TCS have a mutation in the TCOF1 gene. However, some patients exhibit mutations in two new causative genes, POLR1C and POLR1D , which encode subunits of RNA polymerases I and III, that affect ribosome biogenesis. In this study, we examine the role of POLR1C in TCS using zebrafish as a model system. Our data confirmed that polr1c is highly expressed in the facial region, and dysfunction of this gene by knockdown or knock-out resulted in mis-expression of neural crest cells during early development that leads to TCS phenotype. Next generation sequencing and bioinformatics analysis of the polr1c mutants further demonstrated the up-regulated p53 pathway and predicted skeletal disorders. Lastly, we partially rescued the TCS facial phenotype in the background of p53 mutants, which supported the hypothesis that POLR1C-dependent type 3 TCS is associated with the p53 pathway. [ABSTRACT FROM AUTHOR]

Triclosan (TCS) is an active antimicrobial ingredient used in many household products, such as skin creams and toothpaste. It is produced in high volumes, and humans are directly exposed to it and dispose it on a daily basis. TCS has been found to contaminate water worldwide. This study aimed to understand the potential developmental and metabolic abnormalities caused by TCS exposure by using zebrafish as the experimental model. Four developmental stages (70–85% epiboly, 10–12 somite, prim-5, and 5dpf) were selected to perform in situ hybridization staining to investigate the effects of TCS on dorsal ventral patterning, segmentation, brain development, and organ formation. Results showed, in terms of developmental toxicology, that neither phenotypic nor molecular changes were found after 5 days of 250 μg/L TCS exposure. However, such dosage of TCS exposure resulted in lipid droplet accumulation in the yolk sac, which might due to the deregulated mRNA expression level of beta-oxidation transcripts. This study showed that 250 μg/L TCS exposure does not affect normal embryogenesis or organogenesis; however, there are concerns regarding possible impairment of lipid metabolism. [ABSTRACT FROM AUTHOR]

Busulfan (Bu) is widely used in conditioning regimens for infants undergoing allogeneic hematopoietic progenitor cell transplantation (HPCT), but the best approach to administer Bu in this population is still unknown. Here, we report a single-center experience of the use of a test dose to guide dose adjustment of intravenous (i.v.) Bu therapy in infants. Between 2004 and 2013, 33 infants younger than 1 year with nonmalignant conditions received allogeneic peripheral blood or cord blood HPCT after a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, antithymocyte globulin, and 2 single daily doses of i.v. Bu. Pharmacokinetic results of a test dose of i.v. Bu (.8 mg/kg) were used to determine the dose of 2 single daily i.v. Bu regimen doses, adjusted to target an area under the curve (AUC) of 4000 μMol*minute per day in a first cohort (n = 12) and 5000 μMol*minute in a second cohort (n = 21). The mean Bu clearance in our infant patients was found to be 3.67 ± 1.03 mL/minute/kg, and the test dose clearance was highly predictive of the regimen dose clearance. The mean AUC achieved after the first single daily regimen dose was 3951 ± 1239 in the AUC 4000 cohort and 4884 ± 766 for the AUC 5000 cohort. No patient in either cohort developed hepatic sinusoidal obstructive syndrome or seizures attributable to Bu. Primary graft failure occurred in 4 patients and secondary graft failure occurred in 3, predominantly in the AUC 4000 cohort (6 of 7). Among the engrafted patients (n = 28), 16 achieved full donor chimerism and 9 patients attained stable mixed chimerism. Overall survival of patients at 6 years after transplantation was 59.5% for the AUC 4000 cohort and 85.4% for the AUC 5000 cohort, with primary graft failure in the first cohort being a major contributor to morbidity. Logistic regression analysis showed that the risk of graft failure increased significantly if cord blood hematopoietic progenitor cells were used or if total Bu exposure was below 4000 μMol*minute per day for 2 days. The difference in clinical outcomes between the 2 cohorts supports the conclusion that targeting a higher Bu AUC of 5000 μMol*minute per day for 2 days improves donor engraftment in infants with nonmalignant conditions undergoing RIC HPCT without increasing toxicity. Measuring i.v. Bu pharmokinetics using a test dose allows timely adjustment of single daily regimen doses and optimization of total Bu exposure, resulting in an effective and safe regimen for these infants. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ostf1b stimulates cell migration with modulation of EMT phenotype. [•] It activates ROCK1 and MLC2 in RhoA signalling pathway. [•] It induces protein expression of two tight junction proteins. [•] It stimulates the formation of actin fibre. [Copyright &y& Elsevier]

Objective: Signal transducer and activator of transcription 5 (STAT5) is a critical regulator of hematopoietic development and its impaired activation is associated with hematopoietic and immune cell defects. However, much of this information has been learned from knockout mice that still retain the potential for expression of STAT5 proteins that are N-terminally truncated due to alternative internal translation initiation codons. The goal of these studies was to use transplantation-based assays to analyze the degree of STAT5ΔN activity in hematopoietic stem cells (HSC) and throughout lymphomyeloid development. Methods: We have directly compared E14.5 fetal liver cells from mice with potential to express STAT5abΔN (STAT5abΔN/ΔN) with mice completely lacking STAT5a and STAT5b (STAT5abnull/null). We have also utilized retroviral complementation of STAT5abnull/null fetal liver HSC to enforce expression of full-length STAT5a or STAT5a lacking the first 136 amino acids (STAT5aΔN). Results: We report that STAT5 is required for HSC, lymphocyte, and erythrocyte development. We demonstrate that restored expression of STAT5a in STAT5abnull/null HSC provides a strong selective advantage, correcting T- and B-lymphocyte and erythrocyte development. Interestingly, Gr-1+ blood cells were inversely correlated with B lymphocytes and both were normalized by STAT5a expression. In contrast, transduction of STAT5aΔN only provided partial B-lymphocyte development. Conclusions: These studies define the role of STAT5 in maintaining normal lymphoid vs myeloid balance during hematopoiesis and highlight a major role for the N-domain in HSC function. The platform of retroviral complementation described here will be particularly useful for future studies to subdefine the N-domain regions that are critical for hematopoiesis. [Copyright &y& Elsevier]

Myeloablative conditioning (MAC) regimens decrease the risk of relapse in pediatric patients undergoing hematopoietic stem cell transplant (HCT) but cause significant toxicities: transplant-related mortality (TRM) and late effects. Therefore, a MAC regimen that decreases toxicity has the potential to improve overall survival (OS). Busulfan (Bu), fludarabine (Flu), anti-thymocyte globulin (ATG) and 400 cGy of total body irradiation (TBI), a reduced toxicity, MAC regimen was used in pediatric patients. To evaluate the safety and toxicity of this regimen. Secondary objectives included determining OS at 2 and 5 years, and incidence of relapse and GVHD. We prospectively evaluated 40 patients ≤21 years of age undergoing HCT for high-risk leukemias who received dose-adjusted Bu, Flu, ATG and TBI. Bu pharmacokinetics were measured after a test dose and regimen dose 1 to target AUC of 4000-5000 uMol*min/day. Patients were treated between October 2008 and June 2018 (Table 1). OS was 67% and 51% at 2 and 5 years post-HCT, respectively. OS at 2 and 5 years was 70% and 55% for patients with myeloid disease versus 56% and 37% for patients with lymphoid disease, respectively (p=0.18) (Figure 1). Relapse occurred in 11 (28%) at a median of 7 months. TRM was 8% and 13% at 100 days and 1 year post-HCT, respectively. All patients engrafted. >Grade II acute GVHD was seen in 9 (23%); chronic GVHD was seen in 16 (40%). There was no significant impact of age, disease type, donor source or type on HCT outcomes. Long-term toxicities noted were ovarian insufficiency in 8, and short stature, hypothyroidism and learning disabilities in 2 each. Evaluation of Bu AUCs and multivariate analyses are still ongoing. Reduced toxicity, MAC regimen was well tolerated with a low incidence of TRM. This regimen shows a trend toward better efficacy in patients with myeloid disease, however larger studies are needed. [ABSTRACT FROM AUTHOR]

Abstract: Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis when treated with standard chemotherapy. A subset of these infants, particularly those with mixed-lineage leukemia (MLL) rearrangements, has a high likelihood of relapse. Hematopoietic stem cell transplantation (HSCT) performed early in first remission may improve outcome. We present the results of 16 patients with infant ALL who were treated with HSCT in first remission. Six patients were ≤6 months of age at diagnosis, 11 had an initial white blood cell count of >50000/μL, and all patients with determinable cytogenetics had a high-risk karyotype [t(4:11) abnormality or other MLL rearrangement]. All patients received 150 cGy of total body irradiation for 8 doses (1200 cGy). Fifteen of 16 patients received etoposide at 1000 mg/m2 as a continuous infusion over 24 hours and cyclophosphamide at 60 mg/kg/d for 3 days. Eight patients received HSCT from an HLA-identical sibling, and 8, from unrelated cord blood. Twelve (75%) patients remain long-term survivors (median follow-up, 4.7 years). Two patients, 1 of whom had minimal residual disease at HSCT, died after relapse following HSCT. Two patients died of transplant-related causes. The HSCT was well tolerated; 15 patients achieved neutrophil engraftment at a median of 16 days. Acute and chronic graft-versus-host disease were minimal in these patients. These results support the use of HSCT in the treatment of infant ALL, especially when used as consolidation in first remission. The risk of relapse seems to be decreased with this approach. Further work is being performed to determine the long-term effects from this therapy. [Copyright &y& Elsevier]