Wenrong Huang

Unmanipulated HLA-mismatched/haploidentical peripheral blood stem cell transplantation for high-risk hematologic malignancies.

BACKGROUND: Haploidentical hematopoietic stem cell transplantation (HSCT) has been increasingly applied in high‐risk hematologic patients due to the absence of HLA‐matched donors. The aim of this study was to investigate the efficacy and safety of unmanipulated haploidentical allogeneic peripheral blood stem cells transplantation (PBSCT) for hematologic malignancies.

SDF-1/CXCR4 axis in myelodysplastic syndromes: Correlation with angiogenesis and apoptosis

To study the role of SDF-1/CXCR4 axis in MDS, the expression of SDF-1 and CXCR4, VEGF, MVD and apoptosis were measured in MDS. The results showed that the expression of SDF-1 of the low-grade MDS is higher than that of the high-grade MDS and the control. The high-grade MDS had a significantly higher CXCR4 expression on CD34+ cell than low-grade MDS and the control. It was suggested that the SDF-1/CXCR4 axis play an important role in MDS. Apoptosis was significantly increased in low-grade MDS, compared with high-grade MDS. The expression of VEGF and MVD were higher in the high-grade MDS than in the low-grade MDS. There are positive correlations between SDF-1 and apoptosis in the low-grade MDS. For the high-grade MDS, there were positive correlations between CXCR4 and VEGF, and between SDF-1 concentration and MVD. The apoptosis is one of the hallmarks for low-grade MDS and the angiogenesis for high-grade MDS. A refined understanding of the roles that SDF-1/CXCR4 axis and its correlation with angiogenesis and apoptosis play in MDS will fuel the development of therapies that can be targeted to the SDF-1/CXCR4 axis.

Establishment and application of real-time quantitative PCR for diagnosing invasive Aspergillosis via the blood in hematological patients: targeting a specific sequence of Aspergillus 28S-ITS2

BackgroundInvasive aspergillosis (IA) is an important cause of morbidity and mortality in immunocompromised individuals. This study was conducted to identify a desirable target DNA sequence for the diagnosis of aspergillosis using real-time quantitative polymerase chain reaction (qPCR).MethodsGenomic DNA was extracted from Aspergillus, Candida, and bacteria species, and qPCR was applied to validate a partial ribosomal DNA 28S-ITS2 sequence. Ethylenediaminetetraacetic acid-anticoagulated blood samples were collected from 72 febrile hematological patients, while total DNA was isolated from plasma and whole blood for the Aspergillus qPCR. The results were analyzed using a receiver operating characteristic curve. All cases were evaluated using the revised European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) diagnostic criteria.ResultsUse of qPCR yielded positive results for 15 Aspergillus species but negative results for Candida species, bacterial strains, and human DNA. The limit of detection was one copy per microliter of DNA. Analytical sensitivity and specificity were six copies of DNA and 100%, respectively. The standard curve showed that qPCR was reliable for Aspergillus detection and that significantly more DNA copies were obtained from whole blood than from plasma (P < 0.001). At a cut-off value ≥ 25 copies/μL, the diagnostic sensitivity and specificity for IA using 28S-ITS2 qPCR were 90.9% and 73.4%, respectively.ConclusionsThe use of qPCR with whole blood to detect and verify the 28S-ITS2 sequence is a specific and useful way to diagnose IA.

AML1-ETO triggers epigenetic activation of early growth response gene l, inducing apoptosis in t(8;21) acute myeloid leukemia

The t(8;21)(q22;q22) translocation is the most common chromosomal translocation in acute myeloid leukemia (AML), and it gives rise to acute myeloid gene 1 (AML1)–myeloid transforming gene 8 (ETO)‐positive AML, which has a relatively favorable prognosis. However, the molecular mechanism related to a favorable prognosis in AML1–ETO‐positive AML is still not fully understood. Our results show that the AML1–ETO fusion protein triggered activation of early growth response gene l (EGR1) by binding at AML1‐binding sites on the EGR1 promoter and, subsequently, recruiting acetyltransferase P300, which is known to acetylate histones. However, AML1–ETO could not recruit DNA methyltransferases and histone deacetylases; therefore, EGR1 expression was affected by histone acetylation but not by DNA methylation. Both transcription and translation of EGR1 were higher in AML1–ETO‐positive AML cell lines than in AML1–ETO‐negative AML cell lines, owing to acetylation. Furthermore, when AML1–ETO‐positive AML cell lines were treated with C646 (P300 inhibitor) and trichostatin A (histone deacetylase inhibitor), EGR1 expression was significantly decreased and increased, respectively. In addition, treatment with 5‐azacytidine (methyltransferase inhibitor) did not cause any significant change in EGR1 expression. Overexpression of EGR1 inhibited cell proliferation and promoted apoptosis, and EGR1 knockout promoted cell proliferation. Thus, EGR1 could be a novel prognostic factor for a favorable outcome in AML1–ETO‐positive AML. The results of our study may explain the molecular mechanisms underlying the favorable prognosis in AML1–ETO‐positive AML.

Similar incidence of severe acute GVHD and less severe chronic GVHD in PBSCT from unmanipulated, haploidentical donors compared with that from matched sibling donors for patients with haematological malignancies

The features of graft‐versus‐host disease (GVHD) were compared between patients who underwent myeloablative conditioning and received a peripheral blood stem cell transplant (PBSCT) from either a haploidentical donor (HID) or a matched sibling donor (MSD) during the same period of time. The HID group included more patients with advanced disease. Both groups received the same GVHD prophylaxis with the addition of antithymoglobulin (ATG) in HID group. Higher cumulative incidences (CI) of acute GVHD grade 2–4 (35·1% vs. 13·9%, P = 0·003), similar CI of grade 3–4 (14·5% vs. 9·8%, P = 0·595), less 3‐year CI of extensive chronic GVHD (17·1% vs. 41·5%, P = 0·017) and less severe chronic GVHD (5·8% vs. 21·2%, P = 0·049) occurred in the HID group compared with the MSD group. There was no difference in the sites of the involved organs between these two groups. Higher 3‐year CI of non‐relapse mortality (24·0% vs. 10·2%, P = 0·014), relapse (39·0% vs. 22·6%, P = 0·032) and inferior disease‐free survival (45·7% vs. 78·9%, P = 0·000) were recorded in the HID cohort compared with the MSD group. More HID patients had Karnofsky scores above 90 than those in MSD group (P = 0·016). In conclusion, ATG plays a key role in the unmanipulated HID PBSCT protocol, producing better quality of life in survivors.

The efficacy and safety of rabbit anti-thymocyte globulin vs rabbit anti-T-lymphocyte globulin in peripheral blood stem cell transplantation from unrelated donors

The comparative efficacy and safety of antithymocyte globulin (ATG) at fixed doses in patients undergoing allogeneic peripheral blood stem cell transplantation from unrelated donors (UR-PBSCT) has not been evaluated. In this study, the records of 56 patients and 54 patients who received pre-transplant ATG-Thymoglobulin (ATG-T) at a total dose of 10 mg/kg and ATG- Fresenius (ATG-F) at a total dose of 20 mg/kg, respectively, were retrospectively analyzed. ATG-F patients had a significantly lower probability of developing chronic graft-vs-host disease (cGVHD) than those treated with ATG-T (p = 0.04). ATG-F was associated with a non-significant trend towards lower relapse rates and higher survival at 3- and 5-years of follow-up compared with ATG-T. A significantly greater proportion of ATG-T patients experienced chills and high fever than ATG-F patients (p < 0.01). The current findings suggest that ATG-F may more effectively and safely prevent cGVHD without increasing relapse rates in patients undergoing UR-PBSCT.

Similar outcomes after haploidentical transplantation with post-transplant cyclophosphamide versus HLA-matched transplantation: a meta-analysis of case-control studies

Background Outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PT-Cy) have greatly improved. It remains unknown whether haplo-HCT with PT-Cy was associated with poor outcomes when compared with HLA-matched HCT. To address this issue, we performed a meta-analysis to compare outcomes of haplo-HCT with PT-Cy with those of HLA-matched HCT. Methods A systematic search for case-control studies were performed in PubMed, Embase and Cochrane Library databases. Using a random model, the risk ratios (RRs) and 95% confidence intervals (95% CI) were pooled for the final analysis. Results Nine case-control studies including 2258 patients (827 patients in the haplo-HCT with PT-Cy group, 748 controls from HLA-matched related donors (MRD), and 683 controls from HLA-matched unrelated donors (MUD)) met the inclusion criteria. No differences were found between haplo-HCT with PT-Cy and HLA-matched HCT with regard to acute graft-versus-host-disease (GVHD), non-relapse mortality, relapse, progression free survival and overall survival. However, haplo-HCT with PT-Cy was found to be associated with a lower incidence of moderate to severe chronic GVHD (Haplo vs MRD: RR=0.54; 95% CI=0.39-0.75; Haplo vs MUD: RR=0.70; 95% CI=0.56-0.88). Conclusions The results of this meta-analysis suggest that haplo-HCT with PT-Cy can achieve comparable outcomes with those of HLA-matched HCT. Haploidentical donors can be a feasible and valid alternative when conventional HLA-matched donors are unavailable.BACKGROUND Outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PT-Cy) have greatly improved. It remains unknown whether haplo-HCT with PT-Cy was associated with poor outcomes when compared with HLA-matched HCT. To address this issue, we performed a meta-analysis to compare outcomes of haplo-HCT with PT-Cy with those of HLA-matched HCT. METHODS A systematic search for case-control studies were performed in PubMed, Embase and Cochrane Library databases. Using a random model, the risk ratios (RRs) and 95% confidence intervals (95% CI) were pooled for the final analysis. RESULTS Nine case-control studies including 2258 patients (827 patients in the haplo-HCT with PT-Cy group, 748 controls from HLA-matched related donors (MRD), and 683 controls from HLA-matched unrelated donors (MUD)) met the inclusion criteria. No differences were found between haplo-HCT with PT-Cy and HLA-matched HCT with regard to acute graft-versus-host-disease (GVHD), non-relapse mortality, relapse, progression free survival and overall survival. However, haplo-HCT with PT-Cy was found to be associated with a lower incidence of moderate to severe chronic GVHD (Haplo vs MRD: RR=0.54; 95% CI=0.39-0.75; Haplo vs MUD: RR=0.70; 95% CI=0.56-0.88). CONCLUSIONS The results of this meta-analysis suggest that haplo-HCT with PT-Cy can achieve comparable outcomes with those of HLA-matched HCT. Haploidentical donors can be a feasible and valid alternative when conventional HLA-matched donors are unavailable.

A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

MicroRNA‐9‐1(miR‐9‐1) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that miR‐9‐1 is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying miR‐9‐1 downregulation and the RUNX1‐RUNX1T1 fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. RUNX1‐RUNX1T1 can induce leukemogenesis through resides in and functions as a stable RUNX1‐RUNX1T1‐containing transcription factor complex. In this study, we demonstrate that miR‐9‐1 expression increases significantly after the treatment of RUNX1‐RUNX1T1 (+) AML cell lines with decitabine (a DNMT inhibitor) and trichostatin A (an HDAC inhibitor). In addition, we show that RUNX1‐RUNX1T1 triggers the heterochromatic silencing of miR‐9‐1 by binding to RUNX1‐binding sites in the promoter region of miR‐9‐1 and recruiting chromatin‐remodeling enzymes, DNMTs, and HDACs, contributing to hypermethylation of miR‐9‐1 in t (8; 21) AML. Furthermore, because RUNX1, RUNX1T1, and RUNX1‐RUNX1T1 are all regulated by miR‐9‐1, the silencing of miR‐9‐1 enhances the oncogenic activity of these genes. Besides, overexpression of miR‐9‐1 induces differentiation and inhibits proliferation in t (8; 21) AML cell lines. In conclusion, our results indicate a feedback circuitry involving miR‐9‐1 and RUNX1‐RUNX1T1, contributing to leukemogenesis in RUNX1‐RUNX1T1 (+) AML cell lines.

High expression of MAP7 predicts adverse prognosis in young patients with cytogenetically normal acute myeloid leukemia.

Microtubule-associated protein 7 (MAP7) plays an important role in cancer cells. In this study, we identified the prognostic significance of MAP7 expression in cytogenetically normal acute myeloid leukemia (CN-AML) patients (aged <60 years) based on several microarray datasets. In the first group (n = 129), high MAP7 expression (MAP7high) was associated with adverse overall survival (OS; P = 0.0441) and event-free survival (EFS; P = 0.0114) compared with low MAP7 expression (MAP7low). In addition, the prognostic significance of MAP7 was confirmed by European Leukemia Net (ELN) intermediate-I genetic categories and multivariable analysis. In the second independent group of CN-AML patients (aged <60 years), MAP7high was also associated with adverse OS (n = 88, OS; P = 0.00811). To understand the inherent mechanisms of MAP7’s prognosis, we investigated genome-wide gene/microRNA expression signatures associated with MAP7 expression. Several known oncogenic genes/microRNAs and anti-oncogenic genes/microRNAs were disordered in MAP7high CN-AML patients. In conclusion, MAP7high is an adverse prognostic biomarker for CN-AML, which may be attributed to the distinctive genome-wide gene/microRNA expression and related cell signaling pathways.

Risk Factors and Clinical Outcomes for Patients With Acinetobacter baumannii Bacteremia.

Abstract Acinetobacter (A.) baumannii, an opportunistic nosocomial pathogen that can cause significant morbidity and mortality, has emerged as a worldwide problem. This study aimed to analyze the clinical features and outcomes of patients with A. baumannii bacteremia and determine the factors influencing survival by using 14-day mortality as the primary endpoint.A 6-year retrospective study of 122 cases with monomicrobial A. baumannii bacteremia was conducted in Chinese Peoples Liberation Army (PLA) General Hospital from January 2008 to April 2014. Predictors of 14-day mortality were identified by logistic regression analysis.The overall 14-day mortality rate was 40.2% (49 of 122 patients). Multivariable analysis revealed that independent predictors of 14-day mortality included severity of illness defined by Pitt Bacteremia Score (PBS) (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.340–0.619; P < 0.001), neutropenia (OR, 18.02; 95% CI, 1.667–194.67; P = 0.017), and malignancy (OR, 4.63; 95% CI, 1.292–16.588; P = 0.019). The effect of malignancy was influenced by neutropenia (OR for interaction term, 1.60; 95% CI, 1.15–2.22; P = 0.005). A subgroup analysis revealed that 14-day mortality rate for patients with underlying hematological malignancies and solid tumors was 75% (12/16) and 40% (12/30), respectively. Survival analysis revealed that mortality in patients with hematological malignancies was higher than that in patients with solid tumors (P = 0.032).The outcomes of patients with A. baumannii bacteremia were related to PBS, neutropenia, and malignancy. Compared with solid tumors, patients with hematological malignancies had a higher mortality in the setting of A. baumannii bacteremia.