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Aim: To characterize the actionable biomarker for leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) at the DNA damage repair promoter methylation level. Materials & methods: Bioinformatic analysis and experimental validation were performed to identify the MPNs-LT specific biomarker out of the promoter methylation of 236 DNA damage repair genes with GSE42042 dataset and an in-house cohort of 80 MPNs. Results: Hypermethylation of BRCA2 promoter was characterized as the JAK2 mutation-independent epigenetic marker for MPNs-LT and repressed mRNA and protein expression, leading to olaparib hypersensitivity in the leukemic cells from MPNs-LT. Conclusion: Expressional silence of BRCA2 by promoter methylation compels the homologous recombination deficiency and vulnerability to PARP inhibition and serves as an actionable marker for targeted therapy for MPNs-LT.

This study focused genetic pathogenesis and tumor microenvironment of Epstein-Barr virus (EBV) positive diffuse large B-cell lymphomas (DLBCL) in patients without immunodeficiency. DNA samples from these cases were sequenced by next generation sequencing (NGS) using a selected gene panel. Results revealed that most gene mutations were not specific for EBV positive DLBCL. However, B2M (β2-microglobulin) mutations were significantly increased and HLA-I or HLA-II expression was decreased in these cases, which was related to patient's poor outcome. B2M mutations and deregulation of B2M expression were further confirmed by Sanger sequencing and immunohistochemistry. Reducing the infiltration of CD8+ T lymphocytes, related to decreased expression of HLA-I or HLA-II was found in these patients. These results suggest that the mutations of B2M could cause the disruption of the expression and functions of this important subunit of HLA, leading to decreased expression of HLA-I or HLA-II and subsequently to reduce T lymphocyte infiltration in tumor tissues. The consequence of this event lessens the recognition and elimination of EBV+ tumor cells by host immunity and paves the way for the host immune tolerance to EBV+ tumor cells by evading immune recognition and escaping the T lymphocyte killing.

Introduction Genetic landscape, disease characteristics and clinical outcomes of young adults with myeloproliferative neoplasms (MPNs) were reported. However, data on patient-reported outcomes (PROs) in young adults with MPNs were rare. Methods We conducted a multicenter, cross-sectional study to compared the PROs in respondents with thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) by age at survey, including the young group (18-40 years), middle-aged group (41-60 years), and elderly group (> 60 years). Results Of the 1664 respondents with MPNs, 349 (21.0%) were young including 244 (69.9%) with ET, 34 (9.7%) with PV and 71 (20.3%) with MF. In multivariate analyses the young groups with ET and MF were associated with the lowest MPN-10 scores among the 3 age groups; those with MF, highest proportion of reporting negative impact of disease and therapy on their daily life and work. The young groups with MPNs had the highest physical component summary scores, but the lowest mental component summary scores in those with ET. The young groups with MPNs were most concerned about fertility; those with ET, treatment-related adverse events and long-term efficacy of treatment. Conclusions We concluded that young adults with MPNs have different PROs compared with middle-aged and elderly patients.

Background The nucleoporin 98 (NUP98)-paired related homeobox 1 (PMX1) fusion gene, which results from t(1;11)(q23;p15), is rare in patients with acute myeloid leukemia (AML). Currently, only two cases of chronic myeloid leukemia in the accelerated phase or blast crisis and three cases of therapy-related AML have been reported. Here, we first report a patient with de novo AML carrying the NUP98-PMX1 fusion gene. Case presentation A 49-year-old man diagnosed with AML presented the karyotype 46,XY,t(1;11)(q23;p15)[20] in bone marrow (BM) cells. Fluorescence in situ hybridization analysis using dual-color break-apart probes showed the typical signal pattern. Reverse transcription-polymerase chain reaction (RT-PCR) analysis suggested the presence of the NUP98-PMX1 fusion transcript. The patient received idarubicin and cytarabine as induction chemotherapy. After 3 weeks, the BM aspirate showed complete remission, and the RT-PCR result for the NUP98-PMX1 fusion gene was negative. Subsequently, the patient received three cycles of high-dose Ara-c as consolidation chemotherapy, after which he underwent partially matched (human leukocyte antigen–DP locus mismatch) unrelated allogeneic hematopoietic stem cell transplantation (HSCT). The follow-up period ended on September 30, 2020 (6 months after HSCT), and the patient exhibited no recurrence or transplantation-related complications. Conclusion This is the first report of a patient with de novo AML carrying the NUP98-PMX1 fusion gene. The reported case may contribute to a more comprehensive profile of the NUP98-PMX1 rearrangement, but mechanistic studies are warranted to fully understand the role of this fusion gene in leukemia pathogenesis.

Morphological analysis of the bone marrow is an essential step in the diagnosis of hematological disease. The conventional analysis of bone marrow smears is performed under a manual microscope, which is labor-intensive and subject to interobserver variability. The morphological differential diagnosis of abnormal lymphocytes from normal lymphocytes is still challenging. The digital pathology methods integrated with advances in machine learning enable new diagnostic features/algorithms from digital bone marrow cell images in order to optimize classification, thus providing a robust and faster screening diagnostic tool. We have developed a machine learning system, Morphogo, based on algorithms to discriminate abnormal lymphocytes from normal lymphocytes using digital imaging analysis. We retrospectively reviewed 347 cases of bone marrow digital images. Among them, 53 cases had a clinical history and the diagnosis of marrow involvement with lymphoma was confirmed either by morphology or flow cytometry. We split the 53 cases into two groups for training and testing with 43 and 10 cases, respectively. The selected 15,353 cell images were reviewed by pathologists, based on morphological visual appearance, from 43 patients whose diagnosis was confirmed by complementary tests. To expand the range and the precision of recognizing the lymphoid cells in the marrow by automated digital microscopy systems, we developed an algorithm that incorporated color and texture in addition to geometrical cytological features of the variable lymphocyte images which were applied as the training data set. The selected images from the 10 patients were analyzed by the trained artificial intelligence-based recognition system and compared with the final diagnosis rendered by pathologists. The positive predictive value for the identification of the categories of reactive/normal lymphocytes and abnormal lymphoid cells was 99.04%. It seems likely that further training and improvement of the algorithms will facilitate further subclassification of specific lineage subset pathology, e.g., diffuse large B-cell lymphoma from chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma or even hairy cell leukemia in cases of abnormal malignant lymphocyte classes in the future. This research demonstrated the feasibility of digital pathology and emerging machine learning approaches to automatically diagnose lymphoma cells in the bone marrow based on cytological-histological analyses.

The pathogenesis of central nervous system involvement (CNSI) in patients with acute lymphoblastic leukaemia (ALL) remains unclear and a robust biomarker of early diagnosis is missing. An untargeted cerebrospinal fluid (CSF) metabolomics analysis was performed to identify independent risk biomarkers that could diagnose CNSI at the early stage. Thirty-three significantly altered metabolites between ALL patients with and without CNSI were identified, and a CNSI evaluation score (CES) was constructed to predict the risk of CNSI based on three independent risk factors (8-hydroxyguanosine, l-phenylalanine and hypoxanthine). This predictive model could diagnose CNSI with positive prediction values of 95.9% and 85.6% in the training and validation sets respectively. Moreover, CES score increased with the elevated level of central nervous system (CNSI) involvement. In addition, we validated this model by tracking the changes in CES at different stages of CNSI, including before CNSI and during CNSI, and in remission after CNSI. The CES showed good ability to predict the progress of CNSI. Finally, we constructed a nomogram to predict the risk of CNSI in clinical practice, which performed well compared with observed probability. This unique CSF metabolomics study may help us understand the pathogenesis of CNSI, diagnose CNSI at the early stage, and sequentially achieve personalized precision treatment.

This paper investigates the spatial behavior of the solutions of the generalized heat conduction equations on a semi-infinite cylinder by means of a first order differential inequality. We consider three kinds of semi-infinite cylinders with boundary conditions of Dirichlet type. For each cylinder we prove the Phragmén-Lindelöf alternative for the solutions. In the case of decay we also present a method for obtaining explicit bounds for the total energy.

Extranodal involvement is recognized as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, the prognostic differences of patients with refractory/relapsed (R/R) nodal and extranodal DLBCL in the chimeric antigen receptor T cell (CART) therapy era are still unclear.In this study, 18 R/R nodal DLBCL (R/R N-DLBCL) and 19 R/R extranodal DLBCL (R/R EN-DLBCL) were enrolled to compare clinical outcomes.The median follow-up time was 13 (range, 1-47) months and one-year progression-free survival (PFS; 83.3% vs. 42.1%, P = 0.008) and one-year overall survival (OS; 94.4% vs. 63.2%, P = 0.020) were significantly different between nodal and extranodal patients. In the multivariable Cox regression analysis, R/R EN-DLBCL was associated with worse PFS (hazard ratio [HR] = 4.263, P = 0.018) and OS (HR = 9.589, P = 0.034) compared to R/R N-DLBCL. Additionally, autologous hematopoietic stem cell transplantation (ASCT) combined with CART therapy (ASCT + CART) was correlated with better PFS (HR = 0.164, P = 0.003) compared to CART treatment alone.The clinical outcomes of R/R EN-DLBCL were worse than R/R N-DLBCL in patients receiving CART therapy and ASCT + CART therapy is a promising alternative treatment for patients with R/R EN-DLBCL.

Aim: Autologous hematopoietic stem cell transplantation (ASCT) is the standard-of-care curative treatment for relapsed or refractory diffuse large B-cell lymphoma (RR-DLBCL), but the relapse rate is usually high. Materials & methods: In this study, we treated 14 RR-DLBCL patients by combining ASCT and anti-CD19 chimeric antigen receptor T-cell therapy. Results: Eleven (78.57%) patients achieved complete or partial remission. Median duration of progression-free survival was 14.82 months (95% CI: 0.00–31.20 months) with 6-month progression-free survival rate of 64.29% (95% CI: 39.18–89.40%). Median overall survival was not achieved, with 1-year overall survival rate of 65.48% (95% CI: 36.00–94.96%). No neurotoxicity was observed. Conclusion: Our study demonstrated safety and feasibility of ASCT and anti-CD19 chimeric antigen receptor T-cell treatment for RR-DLBCL patients.

Background Several studies have used CD157 in white blood cells with or without proaerolysin (fluorescein-labeled proaerolysin [FLAER])-based flow cytometry assays in the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). Methods We designed a seven-color CD marker panel comprising FLAER, CD15, CD64, CD24, CD14, CD157, and CD45 to verify CD157's clinical applicability and diagnostic performance in a clinical setting. Results A total of 356 samples were tested. These included 43 PNH-positive samples and 313 PNH-negative samples. PNH clones confirmed by the CD157/FLAER combination were almost identical in size to the clones detected by the CD24/CD14/FLAER combination, and the accuracy of the CD157/FLAER combination was 100% in granulocytes and 99.7% in monocytes. Substitution of FLAER with CD157 resulted in 1.9% and 3.5% false-positives in granulocytes and monocytes, respectively. The accuracy was 98.3% and 96.9% in granulocytes and monocytes, respectively. Moreover, the loss of CD157 expression in granulocytes and monocytes was commonly observed in non-PNH patients. Some monocytes in non-PNH patients had weak expression of CD14 but normal expression of FLAER. In this study, PNH clones in granulocytes were always lower than those in matched monocytes. Conclusions We performed the first prospective exploration of the clinical usefulness of FLAER and CD157 in simultaneously recognizing PNH clones in granulocytes and monocytes and verified the applicability of CD157 in substitute for both CD14 and CD24. In the conditions where FLAER is not available, substitution of FLAER with CD157 is acceptable for the identification of PNH clones under the premise of giving full attention to the potential for false-positives.

Objective:. A sequencing panel consisting of 50 genes was customized to reveal the potential molecular land-scapes of essential thrombocytosis, polycythemia vera, and primary myelofibrosis in Chinese patients with myeloproliferative neoplasm (MPN). Methods:. Sixty-five MPN patients (38 with essential thrombocytosis, 21 with polycythemia vera, and 6 with primary myelofibrosis), including 12 triple-negative patients, were recruited and were screened for their mutational spectrum using next-generation sequencing technology in this retrospective observational study. This study was approved by the Institutional Review Board of Changhai Hospital, Naval Military Medical University, China. Results:. In addition to the typical driver mutations in JAK2, CALR, and MPL, pathogenic mutations in 15 other genes were frequently detected among the 65 patients with MPN. The 15 mutated genes were TET2, EZH2, ASXL1, MIR662, MLH1, MLH3, SF3B1, MSH6, BARD1, DNMT3A, KIT, MSH2, RUNX1, TP53, and NRAS in this order according to the mutational frequency detected. The average number of mutated genes was 1.2 genes per patient, while in the 12 triple-negative patients with MPN (ie, patients that lack the JAK2, CALR, or MPL mutations), at least one of the 15 pathogenic mutations was detected for each patient. Interestingly, 4 single nucleotide polymorphisms (rs4858647, rs9376092, rs58270997, rs621940) that might be correlated to individual susceptibility to myeloproliferative neoplasm were identified among the 65 patients. We also found that single nucleotide polymorphism and/or single nucleotide variation mutations occurred in multiple loci of mismatch repair-related genes, which might contribute to the development of MPN. Conclusion:. Our study confirms the importance of the previously known MPN relative genes and, more importantly, provides some new and potentially valuable information about mutations associated with MPNs.

Acute myeloid leukemia (AML) patients relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have a poor prognosis. Cytogenetic evolution (CGE) has been investigated and found to have an important impact on the prognosis of relapsed leukemia, but its impact on AML patients relapsing after transplantation remains controversial. In this study, we analyzed 34 AML patients relapsing after allo-HSCT, among whom 14 developed additional abnormalities in chromosomal karyotype after leukemia recurrence (CGE group) and 20 patients did not (non-CGE group). We found that the cytogenetic characteristics were much more complex at relapse in the CGE group, and the acquisition of aberrations at relapse most commonly involved chromosome 11. The 6-month post-relapse overall survival (PROS) of the CGE group was significantly lower than that of the non-CGE group (21.4% versus 50.0%, P = 0.004). The CGE group also showed a trend of worse 2-year OS (7.1% versus 28.6%, P = 0.096). In the multivariate analyses, the occurrence of chronic graft-versus-host disease (HR 0.27 [95% CI, 0.11-0.68], P = 0.006) and a reduced-intensity FBA conditioning regimen (HR 0.42 [95% CI, 0.18-0.98], P = 0.045) were found to be two independent factors for a better PROS, whereas CGE (HR 3.16 [95% CI, 1.42-7.05], P = 0.005) was associated with a worse PROS. In conclusion, CGE was associated with a poor prognosis in AML patients who relapsed after allo-HSCT, and the importance of monitoring karyotype changes after transplantation should be noted.

We explored variables associated with patient-reported outcomes (PROs) including symptom burden, impact on daily life and work, obstacles during therapy, satisfaction level with therapy, and health-related quality of life in 1500 respondents with myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) in a multicenter, cross-sectional study across China, a representative of the developing countries. In multivariate analyses, urban household registration and higher education level were significantly-associated with no symptoms at diagnosis in respondents with ET or MF. CALR mutation was significantly-associated with lower MPN-10 scores in respondents with MF. Higher MPN-10 scores were significantly-associated with negative impact on daily life and work as well as lower satisfaction level in respondents with ET, PV and MF. Receiving ruxolitinib was significantly-associated with high satisfaction and satisfaction in respondents with MF. In addition, other demographics and clinical variables were also impacting PROs.

Background: The objective is to study the molecular mechanism(s) underlying cardiac troponin I autoantibody (cTnIAAb) binding to cardiomyocyte and resultant myocardial damage/dysfunction. Methods: cTnIAAb was purified from serum of 10 acute myocardial infarction (AMI) patients with left ventricular remodeling. Recombinant human cTnI was used to generate three mouse-derived monoclonal anti-cTnI antibodies (cTnImAb1, cTnImAb2, and cTnImAb3). The target protein in cardiac myocyte membrane bound to cTnImAb and effect of cTnIAAb and cTnImAb on apoptosis and myocardial function were determined. Findings: We revealed that cTnIAAb/cTnImAb1 directly bound to the cardiomyocyte membraneI±-Enolase (ENO1) and triggered cell apoptosis via increased expression of ENO1 and Bax, decreased expression of Bcl2, subsequently activating Caspase8, Caspase 3, phosphatase and tensin homolog (PTEN) while inhibiting Akt activity. This cTnIAAb-ENO1-PTEN-Akt signaling axis contributed to increased myocardial apoptosis, myocardial collagen deposition, and impaired systolic dysfunction. Interpretation: cTnIAAb is not only the independent risk factor of ventricular remodeling after myocardial injury in patients with AMI, but also involved in the process of ventricular remodeling. Funding Statement: This research was supported by the National Natural Science Foundation of China (Grant#: 81260026) and the Doctoral Innovation Fund from Second military Medical University of China. Declaration of Interests: The authors state: "None." Ethics Approval Statement: This study was approved by the Medical Ethics Committee at Changhai Hospital and Changcheng Hospital Affiliated to Nanchang University and patients enrolled provided signed informed consent. The animal protocol was planned in compliance with the animal protection, animal welfare, and ethical principles and was approved by the IACUC of the Second Military Medical University.

BACKGROUND Graft rejection and graft versus host disease (GvHD) have impeded the success of hematopoietic cell transplantation for severe aplastic anemia (SAA) patients. There is no sufficient data to identify the outcomes of peripheral blood stem cell transplantation (PBSCT) in SAA patients, especially for adult SAA patients. The aim of this study was to evaluate the outcomes of adult SAA patients undergoing PBSCT with the FCA regimen. The FCA regimen includes fludarabine, cyclophosphamide, and anti-thymocyte globulin (ATG). MATERIAL AND METHODS We report our experience with 46 adult SAA patients who underwent PBSCT with the FCA regimen. Thirty SAA patients who received only cyclophosphamide and ATG (CA) regimen were used as controls. Complications and survival outcomes were evaluated and compared. RESULTS There was a significantly higher percentage of patients who achieved >95% donor chimerism by day 30 in the FCA group. The 5-year event-free survival (EFS) rate in the FCA group was higher than that in the CA group (95.4% versus 73.3%). In addition, the 5-year rejection rate (RR) in the FCA group was lower than that in the CA group (4.6% versus 23.6%). A multivariable model identified the FCA regimen as an independent factor affecting EFS and RR. However, GvHD and serious infection did not differ between the 2 groups. For patients with an unrelated donor, the FCA regimen had a higher EFS and a lower RR than the CA regimen. CONCLUSIONS The FCA regimen for PBSCT in adult SAA patients compared favorably to the CA regimen. It can improve EFS and reduce graft rejection, especially for unrelated donor PBSCT.

The value of chimeric antigen receptor-modified donor lymphocyte infusion (CAR-DLI) is unclear in B-cell acute lymphoblastic leukemia (B-ALL), particularly in patients with relapsed diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, 5 B-ALL patients who relapsed after allo-HSCT received CAR-DLI (CAR-DLI group), and the outcome was compared with 27 relapsed B-ALL patients who received DLI therapy (DLI group). The median complete remission duration of CAR-DLI group was significantly (P=0.020) longer when compared with DLI group: 9 months (range, 2-29) versus 3.2 months (range, 0-17.4). Furthermore, patients receiving CAR-DLI showed significant (P=0.049) survival advantage over DLI group, with median overall survival of 12 months (range, 3-29) and 3.7 months (range, 0-65), respectively. Of note, no patient developed acute graft versus host disease in the CAR-DLI group, while incidence of acute graft versus host disease grades I-II and grades III-IV were 2 (7%) and 4 (14.8%) in the DLI group, respectively. In addition, cytokine release syndrome in CAR-DLI group was manageable. Overall, our study demonstrated that CAR-DLI significantly improved the survival of B-ALL patients relapsed after allo-HSCT, thus indicating that CAR-DLI may represent an alternative and more effective therapy for B-ALL patients with relapsed diseases.

Microsomal epoxide hyrolase 1 (EPHX1) is a critical biotransformation enzyme and participants in both the detoxification and activation of potentially genotoxic epoxides. In this study, we firstly aimed to investigate the role of EPHX1 in the chemoresistance of acute myeloid leukemic cells to aclarubicin (ACM) and mitoxantrone (MIT). EPHX1 mRNA expression and prognosis were measured in acute myeloid leukemia (AML) patients, and the function of EPHX1 in leukemic cell viability and apoptosis induced by ACM and MIT was also measured. Our results found that EPHX1 expression is obviously associated with recurrence rate, overall survival and time of obtaining first complete remission in AML patients. EPHX1 silencing promoted ACM and MIT induced decrease in cell viability and cell apoptosis of HL-60, K562, and THP-1 that was inhibited by EPHX1 overexpression. EPHX1 reduced the susceptibility of leukemic cells to ACM and MIT by regulating drug-metabolizing enzymes (CYP1A1, GSTM1, and GSTT1) and apoptotic signaling (Bax, Bcl-2, Caspase-3, Caspase-9, and PARP1). Moreover, Nrf2 overexpression significantly increased EPHX1 expression and leukemic cell viability and decreased leukemic cell apoptosis. Taken together, we summarized the recent findings about the chemoresistance-promoting role of EPHX1, and the potential of targeting EPHX1 was proposed to counteract drug resistance in leukemia treatment.

The prognosis of acute myeloid leukemia (AML) with normal karyotype is further determined by specific genetic alterations. The optimal post-remission therapy (PRT) in younger patients within this group after first complete remission (CR1) remains to be determined. We report a retrospective evaluation of PRT approaches in 223 patients under the age of 60 years old with intermediate-risk AML in CR1. Patients receiving allogenic hematopoietic stem cell transplantation (alloHSCT) obtained improved overall survival (OS) than patients who treated with chemotherapy (5-year 61.6 ± 5.2% versus 41.1 ± 5.3%, p = 0.004). AlloHSCT led to fewer cases of relapse (hazard ratio [HR] 0.14, p

Background: Some clinical trials have reported that CD19-negative B-cell lymphoma patients responded to CD19 CART therapy. The mechanism of CD19 CART activating in patients with B-cell lymphoma that do not express CD19 by immunohistochemistry (IHC) remains unknown. Methods: 8 CART treated diffuse large B-cell lymphoma (DLBCL) patients and other 90 DLBCL tissues were tested by IHC using 7 anti-CD19 antibodies. Besides, CD19 mRNA and protein of 6 human DLBCL cell lines were assessed using Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western blotting analysis, and CD19 expression was evaluated by IHC as well as flow cytometry (FCM). Results: 6 out of 8 (75%) DLBCL patients who received CD19 CART therapy were identified as CD19-negative by at least one antibody. In the 6 patients, 5 objective responses were seen (response rate, 83.3%). For the 90 DLBCL samples, 68 samples were involved in analysis, and 57 out of 68 (83.8%) samples were assessed as CD19 negative by at least one antibody. IHC assay for 6 DLBCL cell lines showed that 3 cell lines CD19 expression by IHC had inconsistent results with CD19 mRNA and Western blotting assays, while FCM assay for the 6 DLBCL cell lines showed high sensitivity and good concordance to CD19 expression. Antibody HIB19 mean fluorescence intensity showed a positive correlation with CD19 expression (R2=0.8125, P=0.0137). Conclusion: These results demonstrate the mechanism that CD19-negaive B-cell lymphoma patients respond to CD19 CART therapy, suggesting that inclusion or exclusion of lymphoma patients for CD19 CART therapy based on current CD19 IHC seems unwarranted. FCM assay is recommended as a complementary diagnostic method to CD19 IHC.

Additional file 1. Nucleotide sequences of NUP98-PMX1 fusions by Sanger sequencing.

Intermediate risk acute myeloid leukemia (AML) comprises around 50% of AML patients and is featured with heterogeneous clinical outcomes. The study aimed to generate a prediction model to identify intermediate risk AML patients with an inferior survival. We performed targeted next generation sequencing analysis for 121 patients with 2017 European LeukemiaNet-defined intermediate risk AML, revealing 122 mutated genes, with 24 genes mutated in > 10% of patients. A prognostic nomogram characterized by white blood cell count ≥10×109/L at diagnosis, mutated DNMT3A and genes involved in signaling pathways was developed for 110 patients who were with clinical outcomes. Two subgroups were identified: intermediate low risk (ILR; 43.6%, 48/110) and intermediate high risk (IHR; 56.4%, 62/110). The model was prognostic of overall survival (OS) and relapse-free survival (RFS) (OS: Concordance index [C-index]: 0.703, 95%CI: 0.643-0.763; RFS: C-index: 0.681, 95%CI 0.620-0.741), and was successfully validated with two independent cohorts. Allogeneic hematopoietic stem cell transplantation (alloHSCT) reduced the relapse risk of IHR patients (3-year RFS: alloHSCT: 40.0±12.8% vs. chemotherapy: 8.6±5.8%, P= 0.010). The prediction model can help identify patients with an unfavorable prognosis and refine risk-adapted therapy for intermediate risk AML patients.

Summary Documented reports about T helper type 17 (Th17) cells have revealed that Th17 plays a critical role in inflammation and autoimmunity diseases. However, the role of Th17 in cancer remains contradictory. The interplay between Th17 and tumour cells in the tumour microenvironment of primary hepatic carcinoma (PHC) needs to be explored further and the relationship between Th17, regulatory T cells (Tregs) and regulatory B cells (Bregs) has not been defined completely. In this study, numerous experiments were undertaken to elucidate the interaction of Th17 and Treg/Breg cells involved in PHC. Our work demonstrated that an increased Th17 was detected in the peripheral circulation and in tumour tissues in PHC patients. In addition, increases in peripheral blood Th17 corresponded with tumour–node–metastasis (TNM) stage progression. Also, further studies indicated that Th17 cells were promoted by tumour cells in the PHC tumour microenvironment through both contact-dependent and -independent mechanisms, but cell-contact played the major important role in promoting the production and proliferation of Th17. When isolated CD4+CD25+CD127low Tregs and CD4+CD25–CD127+ non-Tregs were cultured with autologous tumour cells, it implied that the phenotype of Th17 and Tregs was modified by tumour cells in the tumour microenvironment. As well as this, Th17 cells were also found to correlate positively with CD4+forkhead box protein 3+ Tregs and CD19+CD5+CD1dhi Bregs in PHC. Notably, Th17 increased synchronically with Tregs and Bregs in PHC. These findings may provide new clues to reveal the mechanisms of immune escape in PHC.

Background: The translocation t(12; 22) (p13;q12) is a recurrent but infrequent chromosome abnormality in human myeloid malignancies. To date, the role of TEL-MN1 fusion in leukemogenic process and drug resistance is still largely unknown. Methods: In the present study, the TEL-MN1 fusion was transfected into HL-60 cells to upregulate TEL-MN1 expression via a retroviral vector. MTT assay was employed to examine cell viability and flow cytometry was performed to evaluate cell apoptosis. Idarubicin was used to treat HL-60 cells for estimating the effect of TEL-MN1 fusion on the chemotherapy resistance. Results: The results showed that overexpression of TEL-MN1 in HL-60 cells could promote cell proliferation, suggesting that TEL-MN1 may be involved in the leukemogenesis process. HL-60 cells treated with idarubicin showed a weakened cell viability, whereas TEL-MN1 overexpression attenuated the idarubicin-induced inhibition of cell viability and acceleration of cell apoptosis of HL-60 cells. Conclusion: Taken together, our results indicated that TEL-MN1 fusion is an oncogene involved in the leukemogenesis process and TEL-MN1 overexpression enhanced resistance of HL-60 cells to idarubicin, which may provide a useful tool for studying the mechanism of leukemogenesis and drug resistance.

No unified immunophenotypic profiles and corresponding analytic strategies have been established for the rapid diagnosis of acute promyelocytic leukemia (APL) using flow cytometry (FCM). Here we describe a characteristic immunophenotypic panel that can rapidly and accurately distinguish APL from other types of adult acute myeloid leukemia (AML) using only FCM. By comparing APL cells and non-APL AML cells that share APL common immunophenotypes (CD34−CD117+HLA−DR−) we found that CD64 was a significant factor that differentiated APL from other AMLs. Further retrospective analyses of 205 APL and 629 non-APL AML patients from different hematology centers showed that either the CD64dim and homoCD13+homo CD33+homoMPO+ (myeloperoxidase) CD11c− panel or the CD64dim and homoCD13+homo CD33+homoMPO+ CD11c+CD10−CD117+ SSChigh (high side scatter signal) panel could distinguish APL from non-APL AML patients with nearly 100% sensitivity, specificity and accuracy. Moreover, relative quantification of CD64 expression enhanced the applicability of our APL diagnostic immunophenotypic panels (ADI-panels) in different hematology centers. Application of the ADI-panels will decrease diagnosis time and improve personalized treatment for APL, a life-threatening disease with very rapid progression.

We investigated the impact of minimal residual disease (MRD) obtained from different approaches on the outcomes of 141 B lymphoblastic leukemia (B-ALL) patients. Among 169 samples with more than 5% blasts by morphology, 3.6% (6/169) were Flow-MRD negative. Of the 212 positive molecular-MRD samples from Ph+ ALL patients, 55 (25.9%) were Flow-MRD negative. Before consolidation or allogeneic stem cell transplantation (allo-HSCT), negative Flow-MRD was associated with improved survival (p = .019 and .041, respectively) for Ph- ALL patients, but not for Ph+ ALL (p = .111 and .812, respectively). There was no difference in overall survival (OS) by achievement of complete molecular response at complete remission (CR, p = .333 and .863, respectively). Our results indicated that the results of MRDs detected with different methods varied. Flow-MRD can be used as a reliable prognostic marker for Ph- ALL patients. MRD either by flow cytometry or quantitative reverse transcription-polymerase chain reaction (qRT-PCR) at CR did not affect OS or DFS for Ph+ ALL.

In this paper, we consider the following reaction diffusion systems with gradient nonlinearity under nonlinear boundary condition { u t = △ u + u p v q − ∣ ∇ u ∣ α , ( x , t ) ∈ Ω × ( 0 , t ∗ ) ; v t = △ v + v r u s − ∣ ∇ v ∣ α , ( x , t ) ∈ Ω × ( 0 , t ∗ ) ; ∂ u ∂ ν = g ( u ) , ∂ v ∂ ν = h ( v ) , ( x , t ) ∈ ∂ Ω × ( 0 , t ∗ ) ; u ( x , 0 ) = u 0 ( x ) , v ( x , 0 ) = v 0 ( x ) , x ∈ Ω where Ω ⊂ R N ( N ≥ 1 ) is a bounded region with smooth boundary ∂ Ω , p , q , r , s ≥ 0 , α > 1 , t ∗ is a possible blow-up time when blow-up occurs. By constructing an appropriate auxiliary functions, and by means of Payne–Weinberger or Scott’s method, a lower bound on blow-up time when blow-up occurs is derived.

BACKGROUND The MRD status detected using multiparameter flow cytometry (MFC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has crucial prognostic value for patients with acute myeloid leukemia (AML) in morphologic complete remission (CR). We designed a novel panel of antibodies to identify aberrant differentiation/maturation profiles of residual leukemia cells in patients who were not diagnosed at our institution, relapsed with an antigenic shift, or lack leukemia-associated immunophenotypes. METHODS We compared the MRD status detected using MFC and real-time quantitative polymerase chain reaction (RT-qPCR) in the same 158 bone marrow samples collected from 44 AML patients carrying leukemia-specific fusion genes. The clinical performance of the MFC-based MRD status was analyzed in 168 AML patients who exhibited morphologic CR (135) or active disease (33) before HSCT. RESULTS Strong concordance was found between MFC-based and RT-qPCR-based MRD status (κ = 0.868). Among the patients displaying CR, the positive MRD status detected using MFC was correlated with a worse prognosis [HRs (P values) for relapse, event-free survival, and overall survival: 4.83 (

Acute myeloid leukemia (AML) is an aggressive clonal malignancy of hematopoietic progenitor cells with a poor clinical outcome. The resistance of leukemia cells to contemporary chemotherapy is one of the most formidable obstacles to treating AML. Combining valproic acid (VPA) with other anti-leukemic agents has previously been noted as a useful and necessary strategy which can be used to specifically induce anticancer gene expression. In the present study, we demonstrated the synergistic antileukemic activities between VPA and cytarabine (Ara‑C) in a retrovirus-mediated murine model with MLL-AF9 leukemia, three leukemia cell lines (THP-1, K562 and HL-60) and seven primary human AML samples. Using RT-qPCR, we noted that the combination of VPA and Ara‑C significantly upregulated Bax expression and led to the arrest of leukemia cell proliferation, sub-G1 DNA accumulation and cell apoptosis, as demonstrated by flow cytometric analysis. Significantly, further experiments revealed that knockdown of Bax expression prevented VPA and Ara‑C‑induced cell apoptosis in THP-1 cells. The results of our present study demonstrated the synergistic antileukemic effect of combined VPA and Ara‑C treatment in AML, and thus we suggest that VPA be used an alternative treatment for AML.