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Post-transplantation cyclophosphamide (PTCy) can reduce the incidence of graft versus host disease (GVHD) and this intervention is often applied on adults with hematologic malignancy. However, the high relapse rate hinders the development of the intervention and data of PTCy used on children with hematologic malignancy remains limited. In order to overcome issue of high relapse rate in PTCy treatment, we used fludarabine (Flu), enhanced dose of cytarabine (Ara-C, 9 g/m2), busulfan (Bu), Cy, anti-thymocyte globulin (ATG) combined with PTCy for an intensified conditioning regimen. A total of 22 children with acute leukemia received intensified PTCy conditioning regimen (PTCy intensified group). We matched with 18 children who received modified Bu-Cy and ATG conditioning regimen in the same period (ATG group). The two-year cumulative incidences of grade II–IV acute GVHD was significantly lower in PTCy intensified group (13.6 ± 7.7% vs 38.9 ± 11.5%, P = 0.048). Two-year GVHD-free relapse free survival (GRFS) in PTCy seems to be better among the increment group despite not being significant (63.3 ± 10.3% vs 35.4 ± 11.9%, P = 0.092). The positive rate of minimal residual disease after transplantation was significantly lower than that before transplantation (20.0% vs 2.5%, P = 0.029). In conclusion, ATG and PTCy combined with Flu-based increased intensity conditioning regimen is effective for acute leukemia in children. It could reduce GVHD rate significantly and potentially improve GRFS. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle cells (VSMCs) contribute to plaque stability. VSMCs are also a major source of CTH (cystathionine gamma-lyase)-hydrogen sulfide (H2S), a protective gasotransmitter in atherosclerosis. However, the role of VSMC endogenous CTH-H2S in pathogenesis of plaque stability and the mechanism are unknown. In human carotid plaques, CTH expression in ACTA2+ cells was dramatically downregulated in lesion areas in comparison to non-lesion areas. Intraplaque CTH expression was positively correlated with collagen content, whereas there was a negative correlation with CD68+ and necrotic core area, resulting in a rigorous correlation with vulnerability index (r = −0.9033). Deletion of Cth in VSMCs exacerbated plaque vulnerability, and were associated with VSMC autophagy decline, all of which were rescued by H2S donor. In ox-LDL treated VSMCs, cth deletion reduced collagen and heightened apoptosis association with autophagy reduction, and vice versa. For the mechanism, CTH-H2S mediated VSMC autophagosome formation, autolysosome formation and lysosome function, in part by activation of TFEB, a master regulator for autophagy. Interference with TFEB blocked CTH-H2S effects on VSMCs collagen and apoptosis. Next, we demonstrated that CTH-H2S sulfhydrated TFEB at Cys212 site, facilitating its nuclear translocation, and then promoting transcription of its target genes such as ATG9A, LAPTM5 or LDLRAP1. Conclusively, CTH-H2S increases VSMC autophagy by sulfhydration and activation of TFEB, promotes collagen secretion and inhibits apoptosis, thereby attenuating atherogenesis and plaque vulnerability. CTH-H2S may act as a warning biomarker for vulnerable plaque. Abbreviations ATG9A: autophagy related 9A; CTH: cystathionine gamma-lyase; CQ: chloroquine; HASMCs: human aortic smooth muscle cells; H2S: hydrogen sulfide; LAMP1: lysosomal associated membrane protein 1; LAPTM5: lysosomal protein transmembrane 5; NaHS: sodium hydrosulfide hydrate; ox-LDL: oxidized-low density lipoprotein; PPG: DL- propagylglycine; TFEB: transcription factor EB; 3-MA: 3-methyladenine; VSMCs: vascular smooth muscle cells. [ABSTRACT FROM AUTHOR]

Background: Both all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL). Methods: In this study, 73 newly diagnosed APL subjects were treated with an ATRA and As2O3 combination treatment in remission induction and post remission therapy. Tumor burden was examined with PCR of the PML-RAR fusion transcripts, and side effects were evaluated by means of clinical examination. Results: The results showed that ATRA/As2O3 combination therapy yielded a CR rate of 94.5% (69/73) with a shorter time to enter CR (median: 27 days; range: 21-43 days). Four cases failed to enter CR; three of these died of cerebral hemorrhage and disseminated intravascular coagulation (DIC) within 72 hours of starting induction therapy, one older patient died of severe pulmonary infection. The early death rate was 5.5% (4/73). All 69 cases that obtained CR remained in good clinical remission after a follow-up of 35-74 months (median: 52 months).The drug toxicity profile with the use of As2O3 showed mainly hepatotoxicity. Liver dysfunction was slight in most cases. There were no severe side effects in long term follow-up. Conclusion: We conclude that APL patients may benefit from the use of the combination of ATRA and As2O3 in either remission induction or consolidation/maintenance. [ABSTRACT FROM AUTHOR]