Yu-Qian Sun

Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center.

Many patients who require allogeneic hematopoietic stem cell transplantation (allo‐HSCT) lack a human leukocyte antigen (HLA)‐matched donor. Recently, a new strategy was developed for HLA‐mismatched/haploidentical transplantation from family donors without in vitro T cell depletion (TCD).

GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR CONTRIBUTES TO DELAYED INFLAMMATORY HYPERALGESIA IN ADJUVANT RAT PAIN MODEL

Neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, are members of the structurally related neurotrophin family that play important roles in pain modulation. Although there are also indications for the involvement of glial cell line-derived neurotrophic factor (GDNF), it is unclear whether and how GDNF is involved in inflammatory pain. In the present study, we studied the expression pattern of GDNF in dorsal root ganglia (DRG) and spinal cord, using confocal microscopy. We demonstrate that GDNF is well associated with nonpeptidergic pain pathway and that GDNF could possibly be anterogradely transported from DRG neurons to superficial spinal cord dorsal horn. We also studied the dynamic changes of GDNF expression in rats during chronic inflammation using injection of complete Freunds adjuvant as a model of chronic pain. We found that GDNF was down-regulated in both dorsal root ganglia and spinal cords 2 weeks after arthritis induction. To assess the impact of this down-regulation on pain transmission, we used a function-blocking antibody against GDNF delivered intrathecally in the same chronic-pain animal models. Injection of this antibody to GDNF produced no immediate effect, but decreased the delayed, bilateral hyperalgesia induced from a unilateral injection of complete Freunds adjuvant. The effect of this antibody coincided with the down-regulation of GDNF immunoreactivity in response to inflammation, suggesting that GDNF supports biochemical changes that contribute to hyperalgesia.

Association of an Impaired Bone Marrow Microenvironment with Secondary Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether abnormalities of the bone marrow (BM) microenvironment are involved in the pathogenesis of PGF is unclear. In the present prospective nested case-control study, 19 patients with secondary PGF, 38 matched patients with good graft function (GGF) after allo-HSCT, and 15 healthy donors (HDs) were enrolled. The cellular elements of the BM microenvironment, including endosteal cells, perivascular cells, and vascular cells, were analyzed by flow cytometry as well as hematoxylin and eosin and immunohistochemical staining in situ. The median time to occurrence of secondary PGF was 90 days post-transplantation (range, 58 to 264 days). The patients with PGF showed markedly hypocellular marrow (10% versus 45% versus 45%; P < .0001) with scattered hematopoietic cells and significantly lower CD34(+) cells (0.07% versus 0.26% versus 0.26%; P < .0001), endosteal cells (4 per high-power field [hpf] versus 16 per hpf versus 20 per hpf; P < .001), perivascular cells (0.008% versus 0.10% versus 0.12%; P < .0001), and endothelial progenitor cells (0.008% versus 0.16% versus 0.18%; P < .0001) compared with GGF allo-HSCT recipients and HDs, respectively. Multivariate analyses revealed that endothelial progenitor cells (odds ratio, 150.72; P = .001) and the underlying disease (odds ratio, 18.52; P = .007) were independent risk factors for secondary PGF. Our results suggest that the impaired BM microenvironment may contribute to the occurrence of secondary PGF post-HSCT.

Controlled, Randomized, Open-Label Trial of Risk-Stratified Corticosteroid Prevention of Acute Graft-Versus-Host Disease After Haploidentical Transplantation

PURPOSE This study evaluated whether a prophylaxis strategy directed by the graft-versus-host disease (GVHD) biomarker might reduce the 100-day incidence of acute GVHD grades II to IV. PATIENTS AND METHODS This controlled, open-label, randomized trial included 228 patients who underwent haploidentical transplantation. On the basis of bone marrow allogeneic graft CD4:CD8 ratios, patients were categorized as low risk (n = 83; group A) or high risk (n = 145). Patients at high risk were randomly assigned to either receive (n = 72; group B) or not receive (n = 73; group C) low-dose corticosteroid prophylaxis. RESULTS The incidence in group B was 21% (95% CI, 11% to 31%) compared with 26% (95% CI, 16%to 36%; P = .43) in group A and 48% (95% CI, 32% to 60%; P < .001) in group C. Low-dose corticosteroid prophylaxis was significantly associated with a relatively low risk of acute GVHD grades II to IV (hazard ratio, 0.66; 95% CI, 0.49 to 0.89; P = .007) and rapid platelet recovery (hazard ratio, 0.30; 95% CI, 0.23 to 0.47; P < .001). The incidence of moderate-to-severe chronic GVHD in group B (21%) was lower than that in both group A (50%; P = .025) and group C (36%; P = .066). The 100-day corticosteroid doses were 205 ± 111 mg in group B, 229 ± 149 mg in group A (P = .256), and 286.54 ± 259.67 mg in group C (P = .016). Compared with group C, group B showed significantly lower incidences of femoral head necrosis (P = .034) and hypertension (P = .015). Infection rates were comparable among these groups. CONCLUSION Our results suggest that risk stratification-directed, low-dose corticosteroid prophylaxis significantly decreased the incidence of acute GVHD grades II to IV, accelerated platelet recovery, and reduced adverse events without increasing infections.

Atorvastatin enhances endothelial cell function in post transplant poor graft function

Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Murine studies suggest that endothelial progenitor cells (EPCs) are preferential supporting cells for hematopoietic stem cells in the bone marrow (BM) microenvironment. Our previous work found that a reduced number of BM EPCs was an independent risk factor for the occurrence of PGF after allo-HSCT. However, little is known about the functional role of BM EPCs and how to improve impaired BM EPCs in PGF. In the current study, we evaluated the function of BM EPCs in subjects with PGF postallotransplant. Moreover, we investigated whether atorvastatin could enhance the number and function of BM EPCs derived from subjects with PGF in vitro. Dysfunctional BM EPCs, which were characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis, were revealed in subjects with PGF. Activation of p38 and its downstream transcription factor cyclic adenosine monophosphate-responsive element-binding protein were detected in BM EPCs from subjects with PGF. Furthermore, the number and function of BM EPCs derived from subjects with PGF were enhanced by atorvastatin treatment in vitro through downregulation of the p38 MAPK pathway. In summary, dysfunctional BM EPCs were observed in subjects with PGF. Atorvastatin treatment in vitro quantitatively and functionally improved BM EPCs derived from subjects with PGF through downregulation of the p38 MAPK pathway. These data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in subjects with PGF postallotransplant.

Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry: a retrospective and prospective analysis.

BackgroundThis study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical allografts.MethodsA retrospective study (n = 339) and a prospective study (n = 340) were performed. MRD was determined using multiparameter flow cytometry.ResultsEither after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings (P < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre-MRDneg versus pre-MRDpos (P = 0.866 and 0.161, respectively). In either the retrospective (n = 65) or the prospective study (n = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT (P < 0.001 and p = 0.017, respectively). Of the patients with pre-MRDpos in either the total (n = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT (P < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI.ConclusionsThe results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect.

Cesium cholate: determination of X-ray crystal structure indicates participation of the ring hydroxyl groups in metal binding.

The crystal structure of cesium cholate, C(24)H(36)(OH)(3) COOCs has been determined with three-dimensional X-ray diffractometer data. It crystallized in the monoclinic space group P2(1) with unit-cell dimensions a = 11.543(5) A, b = 8.614(3) A, and c = 12.662(5) A, beta(deg) = 107.95(2), V = 1197.7 A(3) and Z = 2. The atomic parameters were refined to a final r = 0.0269 and R(omega) = 0.0280 for 2342 observed reflections. Each Cs(+) is coordinated to 7 oxygen atoms from 5 different cholate anions with Cs-O distances ranging from 2.957(4) A to 3.678(5) A. In this crystal, 5 cholates are coordinated with 1 Cs(+), and 5 Cs(+) are coordinated with 1 cholate anion. Carboxyl and all the 3 ring hydroxyl groups of cholate anion participate in binding to Cs(+) simultaneously, and there is no water molecule coordinated with the Cs(+). The pattern of successive rows arranged with polar (p) and non-polar (n) faces in apposition leads to the formation of a sandwich sheet structure with polar and non-polar channels. The Cs ions lie within the polar interior of the sandwich. The H-bond network is reorganized in forming cesium cholate from cholic acid. All the oxygen atoms in cholate anion are involved in H-bonding reciprocally or with water molecules to form an extensive 3-dimensional network of H-bonds. Compared with cholic acid and other similar type of steroids, the coordination structure and H-bonding of Cs cholate crystal are distinct.

The interaction of Co2+ ions and sodium deoxycholate micelles

Abstract To mimic the interaction between divalent metal ions and bile slats in vivo, two groups of coordination complex compounds, crystalline and gel-like, were synthesized in vitro by mixing the aqueous solutions of CoCl 2 with sodium deoxycholate (NaDC) at various concentrations. Structures and compositions of the compounds were investigated using FT-IR, EXAFS, XRD as well as elemental and ICP analysis, respectively. Then the interaction of Co 2+ with deoxycholate in solution was observed by laser light scattering (LLS), Transmission electronic microscope techniques and ICP analysis. Conclusions are (1) the crystalline complexes, Co (DC) 2 ·3H 2 O were obtained by reaction of Co 2+ with mono-molecules of NaDC, and the gel-like complexes, Na n Co m (DC) n +2 m formed by reaction of Co 2+ with NaDC micelles. The gel-like complexes exhibit the non-stoichiometric character; (2) the coordination structures of carboxyl groups with Co 2+ were different between the crystalline and gel-like complexes. In Co(DC) 2 ·3H 2 O complex, the carboxyl groups of deoxycholate coordinated with Co 2+ in chelating and pseudo-chelating modes, but that in bridge mode in the case of Na n Co m (DC) n +2 m complexes. The non-stoichiometric complexes of Na n Co m (DC) n +2 m are formed with a macromolecular structure through the Co 2+ bridges; (3) NaDC can increase the solubility of Co(DC) 2 ·3H 2 O in aqueous solution, and larger micelles (30–80 nm diameter) formed in the supernate. It is a mixed micelle formed by Co 2+ ions bridges connecting with NaDC simple micelles. So these micelles are a new kind of micelle containing two kinds of metal ions; (4) these results are in agreement with those formed under physiological conditions in that the different states such as gel, precipitate, micelles of various structures are present in bile of gallbladder. An ideal model of the interaction between Co 2+ and bile salts in vivo has been proposed.

Haploidentical stem cell transplantation in patients aged 50 yr and older with leukemia: similar outcomes compared to younger adults.

We aimed to analyze the complications and survival associated with myeloablative haploidentical SCT in patients aged ≥50 yr and compare these results with a younger group population.

Aberrant T cell responses in the bone marrow microenvironment of patients with poor graft function after allogeneic hematopoietic stem cell transplantation

AbstractBackgroundPoor graft function (PGF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, whether abnormalities of T cell subsets in the bone marrow (BM) immune microenvironment, including Th17, Tc17, Th1, Tc1, Th2, Tc2 cells and regulatory T cells (Tregs), are involved in the pathogenesis of PGF remains unclear.MethodsThis prospective nested case–control study enrolled 20 patients with PGF, 40 matched patients with good graft function (GGF) after allo-HSCT, and 20 healthy donors (HD). Th17, Tc17, Th1, Tc1, Th2, Tc2 cells, Tregs and their subsets were analyzed by flow cytometry.ResultsA significantly higher proportion of stimulated CD4+ and CD8+ T cells that produced IL-17 (Th17 and Tc17) was found in the BM of PGF patients than in the BM of GGF patients and HD, whereas the percentages of Tregs in PGF patients were comparable to those in GGF patients and HD, resulting in a dramatically elevated ratio of Th17 cells/Tregs in the BM of PGF patients relative to those in GGF patients. Moreover, both CD4+ and CD8+ T cells were polarized towards a type 1 immune response in the BM of PGF patients.ConclusionsThe present study revealed that aberrant T cell responses in the BM immune microenvironment may be involved in the pathogenesis of PGF after allo-HSCT. These findings will facilitate the optimization of immune regulation strategies and improve the outcome of PGF patients post-allotransplant.