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Graft-derived-cell-free DNA (Gcf-DNA) in plasma is a promising biomarker to monitor graft-rejection after liver transplantation (LTx). However, current methods of measuring Gcf-DNA have several limitations including high cost, long turnaround-time and the need to request donor's genetic information. In this study, eleven patients diagnosed with different inborn errors of metabolism (IEMs) who required living-related LTx were enrolled in order to establish a potentially useful noninvasive method to monitor graft damage. Circulating cell-free DNA (cfDNA) was extracted from plasma specimens serially collected at specific time points (day 0, day 1, day 7, day 14, day 30, day 60) after LTx. The distribution of Gcf-DNA fragment sizes was measured using sequencing read lengths and quantified by using Y-chromosome capture methodology in seven sex-mismatched recipients. In the analysis of fragment size distribution, we observed Gcf-DNA exhibited smaller fragment sizes than the recipient-cfDNA. Based on this phenomenon, two fragment sizes (105-145 bp, 160-170 bp) of the cfDNA pool were extracted to enrich Gcf-DNA. Accordingly, the ratio of short fragments to long fragments (S/L-Frag) in cfDNA was calculated. A high S/L-Frag ratio pointed towards an early trend of graft injury when compared to two routine liver function enzymes (ALT and AST) and Gcf-DNA, and it significantly correlated with ALT (P < 0.0001) and AST (P < 0.0001) during full-blown rejection. In conclusion, we established the Gcf-DNA size profile in patients who have undergone living-related LTx and established a potential biomarker to monitor graft function after LTx. [ABSTRACT FROM AUTHOR]

The synthesis and structure determination of atomically precise alloy nanoclusters have attracted much attention in recent research. Herein, we report a new alloy nanocluster Au 24- x Ag x (TBBM) 20 ( x ∼ 1) synthesized via a ligand-exchange-induced size/structure transformation method. Its X-ray structure is obtained successfully and the dopant Ag is found to occupy three special positions in the kernel, rather than equivalently over all the kernel sites. This selective occupancy is interesting and DFT calculation results suggest that the relative oxidation state (rationalized as difference in the charge) of the Ag when doped into the cluster is likely determining the most favorable doping positions. This work provides a new strategy for controlled synthesis of new Au-Ag nanoclusters and also reveals a new scenario for the doping position of Ag atoms in Au-Ag bimetal nanoclusters. [ABSTRACT FROM AUTHOR]

Unrelated umbilical cord blood transplantation (UCBT) for bone marrow failure (BMF) disorders using conditioning regimens without Anti-Thymocyte Globulin (ATG) has been used as an alternative transplantation for emerging patients without matched-sibling donors. Experience with this transplant modality in children is limited, especially as a secondary treatment for transplant failure patients. We retrospectively reviewed 17 consecutive bone marrow failure patients who underwent unrelated umbilical cord blood transplantation in our center and received conditioning regimens of Total Body Irradiation (TBI) or Busulfan (BU) + Fludarabine (FLU) + Cyclophosphamide (CY). Among the 17 BMF patients, 15 patients were treated with first cord blood transplantation and another 2 with secondary cord blood transplantation because of graft failure after first haploidentical stem cell transplantation at days +38 and +82. All patients engrafted with a median donor cell chimerism of 50 % at days +7 (range, 16 %–99.95 %) and finally rose to 100 % at days +30. Median time to neutrophil engraftment was 19 days (range, 12–30) and time to platelet engraftment was 32 days (range, 18–61). Pre-engraftment syndrome (PES) was found in 16 patients (94.11 %, 16/17). Cumulative incidence of grades II to IV acute GVHD was 58.8 % (95 % CI: 32.7–84.9 %), and 17.6 % (95 % CI: 2.6–37.9 %) of patients developed chronic GVHD. The 3-year overall survival (OS) and failure-free survival (FFS) rates were 92.86 ± 6.88 %. UCBT is an effective alternative treatment for bone marrow failure pediatric patients. TBI/BU + FLU + CY regimen ensure a high engraftment rate for unrelated umbilical cord blood transplantation, which overcomes the difficulty of graft failure. Secondary salvage use of cord blood transplantation may still be useful for patients who have failed after other transplantation. [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia (AA) is recognized as an immune-mediated disorder resulting from active destruction of hematopoietic cells in bone marrow (BM) by effector T lymphocytes. Bulk genomic landscape analysis and transcriptomic profiling have contributed to a better understanding of the recurrent cytogenetic abnormalities and immunologic cues associated with the onset of hematopoietic destruction. However, the functional mechanistic determinants underlying the complexity of heterogeneous T lymphocyte populations as well as their correlation with clinical outcomes remain to be elucidated. To uncover dysfunctional mechanisms acting within the heterogeneous marrow-infiltrating immune environment and examine their pathogenic interplay with the hematopoietic stem/progenitor pool, we exploited single-cell mass cytometry for BM mononuclear cells of severe AA (SAA) patients pre- and post-immunosuppressive therapy, in contrast to those of healthy donors. Alignment of BM cellular composition with hematopoietic developmental trajectories revealed potential functional roles for non-canonically activated CD4+ naïve T cells in newly-diagnosed pediatric cases of SAA. Furthermore, single-cell transcriptomic profiling highlighted a population of Th17-polarized CD4+CAMK4+ naïve T cells showing activation of the IL-6/JAK3/STAT3 pathway, while gene signature dissection indicated a predisposition to proinflammatory pathogenesis. Retrospective validation from our SAA cohort of 231 patients revealed high plasma levels of IL-6 as an independent risk factor of delayed hematopoietic response to antithymocyte globulin-based immunosuppressive therapy. Thus, IL-6 warrants further investigation as a putative therapeutic target in SAA. • Mass cytometry revealed CD4+ naïve T cells with hyperactivated JAK3/STAT3 pathway may be invloved in SAA pathogenesis. • scRNA-seq uncovered CD4+ CAMK4+ naïve T cells were associated with aberrant immune activation in SAA development. • Aberrant activation of the IL6/JAK3/STAT3 pathway were seen in Th17-polarized CD4+ CAMK4+ naïve T cells from pediatric SAA. • High levels of baseline serum cytokine IL-6 predict delayed hematopoietic response to IST in SAA. Th17-polarized naïve T cells with IL6/JAK3/STAT3 activation show putative clinical significance in SAA. [ABSTRACT FROM AUTHOR]