BackgroundMolecular analysis is a promising source of clinically useful prognostic biomarkers. The aim of this investigation was to identify prognostic biomarkers for patients with acute myeloid leukemia (AML) by using the gene expression profile dataset from public database.MethodsThe gene expression profile dataset and corresponding overall survival (OS) information of three cohorts of AML patients from GSE12417 and The Cancer Genome Atlas AML project (TCGA-LAML) were included in the present study. Prognostic gene screening was performed by using a survival package, whereas time-dependent receiver operating characteristic (ROC) curve analysis was performed using the survivalROC package.ResultsIn the three cohorts, 11 genes were identified that were significantly associated with AML OS. A linear prognostic model of the 11 genes was constructed and weighted by regression coefficient (β) from the multivariate Cox regression analyses of GSE12417 HG-U133A cohort to divide patients into high- and low-risk groups. GSE12417 HG-U133 plus 2.0 and TCGA-LAML were validation cohorts. Patients assigned to the high-risk group exhibited poor OS compared to patients in the low-risk group. The 11-gene signature is a prognostic marker of AML and demonstrates good performance for predicting 1-, 3-, and 5-year OS as evaluated by survivalROC in the three cohorts.ConclusionOur study has identified an mRNA signature including 11 genes, which may serve as a potential prognostic marker of AML.

BackgroundImprovement of current GVHD prophylactic therapies remains an important goal in the allo-HSCT. We have described a novel prophylaxis regimen in a single institution trial. The Chinese Bone Marrow Transplant Cooperative Group (CBMTCG) initiated a phase II multicenter study.MethodsThe study was designed as a prospective, single arm phase II open-label, multicenter clinical trial. The primary endpoint was improvement of aGVHD by 25% over historical control (40%) in Chinese patients. 508 patients were enrolled. All of the patients received cyclosporine A (CsA), methotrexate (MTX) and mycophenolate mofetil (MMF) (0.5-1.0 g daily for 30 days) as GVHD prophylaxis regimen.ResultsThe primary endpoint was met with cumulative incidences of grades 2 to 4 and grades 3 to 4 aGVHD of 23.2% and 10.3%, respectively. Incidence for cGVHD was 67.4%. The non-relapse mortality (NRM) rate was 18.4% at 2 years. The probabilities of leukemia free survival (LFS) for non-advanced stage and advanced stage patients at 2 years were 69.7% and 44.8% respectively (p = 0.000). Recipient age ≥ 40 years, advanced stage and Busulfan-Fludarabine(BuFlu) conditioning regimen were identified as major risk factors for aGVHD. Recipient age ≥ 40 years, BuFlu conditioning regimens, female donor/male recipient and prior aGVHD were associated with cGVHD. Despite lower RM (relapse mortality), patients with grade 2–4 aGVHD had higher NRM and worse OS and LFS compared to patients with grade 0–1 aGVHD. In contrast, patients with cGVHD had better OS and LFS and lower RM compared to patients without cGVHD.ConclusionThe novel GVHD regimen decreased the risk for aGVHD by 42% without improving the risk for cGVHD compared to historical controls. Development of aGVHD was associated with worse OS and LFS as well as higher NRM. In contrast, cGVHD was associated with improved OS and LFS likely attributed to a GVL effect.

What is known and objectives Augmented renal clearance (ARC) is characterized by enhanced renal clearance, which leads to insufficient vancomycin exposure and treatment failure. In haematologic malignancy patients, determination of optimal vancomycin dosage is essential because of high stake of life‐threatening bacterial infection and increased clearance. The aim of this study was to describe vancomycin pharmacokinetic parameters in haematologic malignancy with augmented renal clearance children and define the appropriate dosing regimen to achieve an AUC0‐24h/MIC ≥400. Methods Hematologic malignancy with ARC children was enrolled in this retrospective study. The vancomycin PPK model was established by non‐linear mixed‐effects modelling programme. Goodness‐of‐fit (GOF) plots, non‐parametric bootstrap, normalized prediction distribution error (NPDE) and visual predictive checks (VPCs) were carried out for internal evaluation of the final model. Monte Carlo simulation method was used to stimulate the optimal dosage regimens. Results Fifty‐three patients with 106 samples were included. A one‐compartment model with first‐order elimination was developed, and the final model was as follows: CL (L/h) = 6.32×（WT/70）0.75 × e0.0467; V(L) = 39.6×(WT/70), where WT denotes weight (kg). The internal validation of the model showed a good prediction performance. Monte Carlo simulation results showed that when MIC was 0.5 mg/L or 1 mg/L, the recommended doses to achieve a target of AUC0‐24h/MIC ≥400 were 25 to 40 and 50 to 75 mg/kg/d, respectively. With decreasing weight, the recommended dosage to achieve an AUC0‐24h/MIC ≥400 increased. What is new and conclusion A one‐compartment vancomycin PPK model was established in haematologic malignancy with augmented renal clearance children with weight with allometric scaling as a significant covariate. When MIC was 1 mg/L, current recommended paediatric dosages were insufficient in haematologic malignancy with augmented renal clearance children and should be increased.

Since disturbance of angiogenesis predisposes to ischemic injuries, attempts to promote angiogenesis have been made to improve clinical outcomes of patients with many ischemic disorders. While hypoxia inducible factors (HIFs) stimulate vascular remodeling and angiogenesis, hyperlipidemia impairs angiogenesis in response to various pro-angiogenic factors. However, it remains uncertain how HIFs regulate angiogenesis under hyperlipidemia. Here, we report that exposure to low-density lipoprotein (LDL) suppressed in vitro angiogenesis of human brain microvascular endothelial cells. Whereas LDL exposure diminished expression of HIF-1α and HIF-2α induced by hypoxia, it inhibited DMOG- and TNFα-induced HIF-1α and HIF-2α expression in normoxia. Notably, in both hypoxia and normoxia, LDL markedly reduced expression of HIF-1β, a constitutively stable HIF subunit, an event associated with NF-κB inactivation. Moreover, knockdown of HIF-1β down-regulated HIF-1α and HIF-2α expression, in association with increased HIF-1α hydroxylation and 20S proteasome activity after LDL exposure. Significantly, the proteasome inhibitor BSc2118 prevented angiogenesis attenuation by LDL through restoring expression of HIFs. Together, these findings argue that HIF-1β might act as a novel cross-link between the HIF and NF-κB pathways in suppression of angiogenesis by LDL, while proteasome inhibitors might promote angiogenesis by reactivating this signaling cascade under hyperlipidemia.

BackgroundTumor protein p53 (TP53) mutations are not only a risk factor in acute myeloid leukemia (AML) but also a potential biomarker for individualized treatment options. This study aimed to investigate potential pathways and genes associated with TP53 mutations in adult de novo AML.MethodsAn RNA sequencing dataset of adult de novo AML was downloaded from The Cancer Genome Atlas database. Differentially expressed genes (DEGs) were identified by edgeR of the R platform. Key pathways and genes were identified using the following bioinformatics tools: gene set enrichment analysis (GSEA), gene ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), Search Tool for the Retrieval of Interacting Genes/Proteins, and Molecular Complex Detection.ResultsGSEA suggested that TP53 mutations were significantly associated with cell differentiation, proliferation, cell adhesion biological processes, and MAPK pathway. In total, 1,287 genes were identified as DEGs. GO and KEGG analysis suggested that upregulation of DEGs was significantly enriched in categories associated with cell adhesion biological processes, Ras-associated protein 1, PI3K–Akt pathway, and cell adhesion molecules. The top ten genes ranked by degree, CDH1, BMP2, KDR, LEP, CASR, ITGA2B, APOE, MNX1, NMU, and TRH, were identified as hub genes from the protein–protein interaction network. Survival analysis suggested that patients with TP53 mutations had a significantly increased risk of death, while the mRNA expression level in patients with TP53 mutation was similar to those carrying TP53 wild type.ConclusionOur findings have indicated that multiple genes and pathways may play a crucial role in TP53 mutation AML, offering candidate targets and strategies for TP53 mutation AML individualized treatment.

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Background: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for hematological disorders. Tacrolimus is widely used after HSCT, but it has highly interindividual variable pharmacokinetics. Population pharmacokinetics (PPK) researches of tacrolimus in children with β-thalassemia major (β-TM) undergoing HSCT are insufficient. Objective: To establish a PPK model of tacrolimus in children with β-TM and optimize initial dosing regimen for achieving target concentration of 5 to 15 ng/mL. Methods: Data on patients aged <18 years were retrospectively collected from January 2017 to December 2018. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed-effects modeling. Results: A data set of 55 patients with 332 concentrations was included. A 2-compartment model could best describe the pharmacokinetics of tacrolimus. The body surface area and gender were significant covariates in the final model. The typical value of clearance, the distribution volume of the central room, the distribution volume of the peripheral room, and the intercompartmental clearance were 5.05L/h, 4.33L, 155L, and 6.22L/h, respectively. The optimal initial dosing regimen of 0.03, 0.04, 0.05, 0.06, and 0.10 mg/kg were appropriate for female children with a weight (WT) of 50 to 10 kg. The regimen of 0.04, 0.05, 0.06, 0.07, and 0.12 mg/kg is suitable for male children with a WT of 50 to 10 kg. The probability of target attainment (PTA) of each regimen reached 91%. Conclusion and Relevance: A stable PPK model of tacrolimus was established. The proposed dosage regimen reached a good PTA, which could provide a reference for tacrolimus therapy.

In the bone marrow (BM), hematopoietic stem and progenitor cells (HSPCs) reside in specialized niches near osteoblast cells at the endosteum. HSPCs that egress to peripheral blood are widely used for transplant, and mobilization is most commonly performed with recombinant human granulocyte colony-stimulating factor (G-CSF). However, the cellular targets of G-CSF that initiate the mobilization cascade and bone remodeling are not completely understood. Here, we examined whether T and B lymphocytes modulate the bone niche and influence HSPC mobilization. We used T and B defective mice to show that G-CSF-induced mobilization of HSPCs correlated with B lymphocytes but poorly with T lymphocytes. In addition, we found that defective B lymphocytes prevent G-CSF-mediated osteoblast disruption, and further study showed BM osteoblasts were reduced coincident with mobilization, induced by elevated expression of dickkopf1 of BM B lymphocytes. BM T cells were also involved in G-CSF-induced osteoclast activation by regulating the Receptor Activator of Nuclear Factor-κ B Ligand/Osteoprotegerin (RANKL/OPG) axis. These data provide evidence that BM B and T lymphocytes play a role in G-CSF-induced HSPC mobilization by regulating bone remodeling.