Erratum: Overexpression of ZEB1 and YAP1 is related to poor prognosis in patients with gliomas with different IDH1 status.

[This corrects the article on p. 138 in vol. 16, PMID: 37559682.].

[Clinical Characteristics and Correlation with Prognosis of DLBCL with Bone Marrow Involvement and Chromosomal Abnormalities].

OBJECTIVE: To investigate the clinical characteristics of diffuse large B-cell lymphoma(DLBCL) patients with bone marrow involvement and chromosome abnormalities, and further analyze the correlation between the degree of chromosome abnormality and prognosis. METHODS: The clinical data of 88 patients diagnosed with DLBCL with bone marrow involvement and complete chromosomal findings in Shanxi Province Cancer Hospital were retrospectively analyzed. The χ2 test was used to analyze their clinical characteristics, and the Kaplan-Meier method was used in PFS and OS, and log-rank method in comparison. RESULTS: Chromosome abnormalities were detected in 31 of the 88 patients(35.2%), 15 of whom had complex karyotype(17.0%). The positive rate of BCL-2, BCL-6, C-MYC and Ki-67≥80% was high in patients with complex karyotype, and most of them are double expressor lymphoma. Survival analysis showed that patients with complex karyotype of DLBCL had poorer PFS and OS compared to those with normal karyotype and 1-2 chromosomal abnormalities. CONCLUSION: In DLBCL patients with bone marrow involvement and chromosome abnormalities, patients with complex karyotype have a shorter survival time.

Overexpression of ZEB1 and YAP1 is related to poor prognosis in patients with gliomas with different IDH1 status.

OBJECTIVE: Whether there is a correlation between zinc-finger E-box-binding homolog 1 (ZEB1) and Yes-associated protein 1 (YAP1) with clinical outcome in gliomas remains unclear. Hence, this study aimed to investigate the effects of ZEB1 and YAP1 on the prognosis of human gliomas and its relationship with the isocitrate dehydrogenase 1 (IDH1) gene state. METHODS: Immunohistochemical staining was used to record the expression levels of ZEB1, YAP1, and p-YAP1 in 122 cases of low-grade glioma (LGGs) and 69 cases of glioblastoma (GBMs). The correlations of ZEB1 and YAP1 with pathological data were determined by Pearson's Chi-square test. Spearman correlation analysis was then used for analyzing the relationship among YAP1, ZEB1, and IDH1 gene status. The effects of ZEB1 and YAP1 on prognosis were investigated through survival analysis. RESULTS: We detected high ZEB1 expression levels in 29 LGGs (23.8%) and 39 GBMs (56.5%), and high YAP1 expression levels in 22 LGGs (18.0%) and 44 of GBM (63.8%). These results revealed that the protein expression levels of ZEB1 and YAP1 were higher in GBM (P < 0.001). There was a significantly positive correlation between ZEB1 and YAP1 (P < 0.001; r = 0.533). High ZEB1 expression was related to tumor grade (P < 0.001) and Ki-67 (P = 0.0037). YAP1 overexpression was correlated with Ki-67 (P < 0.001), P53 (P = 0.009), tumor grade (P < 0.001), and tumor location (P = 0.018). Patients with ZEB1 and YAP1 high expression had worse overall survival (OS) (P < 0.001). The multivariate analysis showed that YAP1 was an independent prognostic factor for OS. In the LGG group, worse OS were observed in glioma patients with elevated YAP1 expression level. Spearman correlation analysis revealed no association between ZEB1 expression and IDH1 state (P = 0.360; r = -0.084), and YAP1 expression had a negative correlation with IDH1 mutation (P < 0.001, r = -0.364). CONCLUSIONS: Our study showed that ZEB1 and YAP1 were significantly activated in GBM, and patients with high ZEB1 and YAP1 expression had worse OS. ZEB1 expression was significantly correlated with YAP1 in glioma. ZEB1 and YAP1 coexpression may serve as a useful prognostic biomarker for glioma, and aberrant YAP1 expression may be associated with IDH1 gene state.

A national, multicenter, retrospective study of Castleman disease in China implementing CDCN criteria.

Background: Castleman disease (CD) is a group of rare and heterogenous lymphoproliferative disorders including unicentric CD (UCD), human herpesvirus-8(HHV-8)-associated multicentric CD (HHV8-MCD), and HHV-8-negative/idiopathic multicentric CD (iMCD). Knowledge of CD mainly comes from case series or retrospective studies, but the inclusion criteria of these studies vary because the Castleman Disease Collaborative Network (CDCN) diagnostic criteria for iMCD and UCD were not available until 2017 and 2020, respectively. Further, these criteria and guidelines have not been systematically evaluated. Methods: In this national, multicenter, retrospective study implementing CDCN criteria, we enrolled 1634 CD patients (UCD, n = 903; MCD, n = 731) from 2000 to 2021 at 40 Chinese institutions to depict clinical features, treatment options, and prognostic factors of CD. Findings: Among UCD, there were 162 (17.9%) patients with an MCD-like inflammatory state. Among MCD, there were 12 HHV8-MCD patients and 719 HHV-8-negative MCD patients, which included 139 asymptomatic MCD (aMCD) and 580 iMCD meeting clinical criteria. Of 580 iMCD patients, 41 (7.1%) met iMCD-TAFRO criteria, the others were iMCD-NOS. iMCD-NOS were further divided into iMCD-IPL (n = 97) and iMCD-NOS without IPL (n = 442). Among iMCD patients with first-line treatment data, a trend from pulse combination chemotherapy toward continuous treatment was observed. Survival analysis revealed significant differences between subtypes and severe iMCD (HR = 3.747; 95% CI: 2.112-6.649, p < 0.001) had worse outcome. Interpretation: This study depicts a broad picture of CD, treatment options and survival information in China and validates the association between the CDCN's definition of severe iMCD and worse outcomes, requiring more intensive treatment. Fundings: Beijing Municipal Commission of Science and Technology, CAMS Innovation Fund and National High Level Hospital Clinical Research Funding.

TRIM52 aggravated inflammation and pyroptosis in dextran sulfate sodium-induced inflammatory bowel disease through activation of the TLR4/NF-κBs pathway.

INTRODUCTION: Inflammatory bowel disease (IBD), which mainly leads to diarrhea, fatigue, stool blood, abdominal pain, and cramping, is threatening public health. Tripartite motif-containing 52 (TRIM52) has been reported to play an important role in inflammatory responses via activating the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. However, the causes of IBD need to be elucidated, and the function of TRIM52 in IBD remains unclear. Here, we demonstrated that TRIM52 aggravated inflammation and pyroptosis in dextran sulfate sodium (DSS)-induced IBD by activating TLR4/NF-κBs pathway. METHODS: The colitis model was established on mice through DSS induction. For the TRIM52 knockdown, the mice were infected with a recombinant adenoviral vector expressing sgRNAs targeting TRIM52. RT-qPCR, western blot, and immunohistochemistry were performed to verify TRIM52 expression in DSS-induced IBD. The body weight, disease activity index, colon length, and H&E staining were used to assess the IBD symptoms in mice with TRIM52 knockdown. The inflammatory responses were examined by RT-qPCR and ELISA measuring tumor necrosis factor-α (TNF-α), inter-leukin 6 (IL-6), and interleukin 1ß (IL-1ß). Furthermore, the pyroptosis in colon tissue was detected by western blot. Finally, the TLR4/NF-κBs pathway activity was also examined by western blot. RESULTS: TRIM52 expression was up-regulated in DSS-induced IBD, and knockdown of TRIM52 could alleviate the symptoms of IBD. TRIM52 knockdown retarded DSS-induced inflammatory response and inhibited DSS-induced pyroptosis in colon tissue. In addition, TRIM52 played a role in activating TLR4/NF-κBs pathway. CONCLUSION: Knockdown of TRIM52 alleviated inflammation and pyroptosis in IBD by regulating TLR4/NF-κBs pathway. TRIM52 is expected to be a novel diagnostic indicator for IBD and a target of therapeutic treatment.

The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients.

ASAP3 is involved in a variety of biological activities, including cancer progression in humans. In adult glioma, we explore the effects of ASAP3 and NOTCH3 and their relationships on prognosis. The Oncomine, TIMER, and Gene Expression Profiling Interactive Analysis databases were used to investigate ASAP3 expression. Immunohistochemistry was used to assess the levels of ASAP3 and NOTCH3 expressions. The effects of ASAP3 and NOTCH3 on prognosis were assessed using survival analysis. The results revealed that the amount of ASAP3 mRNA in gliomas was much higher than in normal tissue (P < 0.01). Glioma patients with high ASAP3 mRNA expression had a worse overall survival and progression-free survival. ASAP3 overexpression is directly associated with the NOTCH signaling system. Immunohistochemistry revealed that ASAP3 and NOTCH3 were overexpressed in glioblastomas (GBMs). ASAP3 expression was associated with age, recurrence, tumor resection, postoperative chemoradiotherapy, World Health Organization (WHO) grade, and Ki-67 expression. ASAP3 expression was related to the isocitrate dehydrogenase-1 mutation in low-grade glioma. Gender, local recurrence, tumor resection, postoperative radio-chemotherapy, WHO grade, recurrence, and ATRX expression were all associated with NOTCH3 expression. ASAP3 was shown to be positively associated with NOTCH3 (r = 0.337, P = 0.000). Therefore, ASAP3 and NOTCH3 as oncogene factors have the potential to be prognostic biomarkers and therapeutic targets in adult glioma.

Thymosin ß4 increases cardiac cell proliferation, cell engraftment, and the reparative potency of human induced-pluripotent stem cell-derived cardiomyocytes in a porcine model of acute myocardial infarction.

Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.

[Evaluation of GELTAMO-IPI for Patients with Diffuse Large B-cell Lymphoma].

OBJECTIVE: To evaluate the prognostic value of GELTAMO-IPI for patients with diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 238 newly diagnosed DLBCL patients treated in Shanxi Cancer Hospital from September 2011 to March 2016 were collected retrospectively, the risk stratification and prognostic evaluation of the patients were analyzed according to GELTAMO-IPI. Progression-free survival (PFS) and overall survival (OS) of the patients were analyzed by the Kaplan-Meier method, COX regression analysis was used to compare the risk of death and progress in each risk group. Harrell's C statistics was used to compare the prognostic stratification ability of each model. RESULTS: The 3-year OS rate statistics showed that both IPI and GELTAMO-IPI could distinguish low risk group and Low-intermediate risk group, but the prognosis stratification ability of IPI was better (IPI: HR=5.085, P<0.05; GELTAMO-IPI; HR=4.639, P>0.05). GELTAMO-IPI could distinguish High-intermediate risk group from high risk group (GELTAMO-IPI: HR=2.966, P<0.05; 3 years OS rate was 34.5%), but the ability of IPI to identify high risk groups was weak (3 years OS>50%). The results of Harrell's C statistics showed the C-index of IPI and GELTAMO-IPI was 0.687 and 0.721 (P<0.001); the C-index of the predicted PFS was 0.672 and 0.700 (P<0.001). It was suggested that the prognostic stratification ability of GELTAM0-IPI be superior to that of IPI, R-IPI, NCCN-IPI. CONCLUSION: GELTAMO-IPI can make a clear distinction between DLBCL patients with different prognosis, especially for high-risk patients, and the prognostic stratification ability of GELTAMO-IPI is significantly better than that of IPI.

Expression of YAP1 and pSTAT3-S727 and their prognostic value in glioma.

AIMS: A growing research demonstrated that YAP1 played important roles in gliomagenesis. We explored the expression of YAP1 and STAT3, the relationship between them and the effect of YAP1, STAT3 on prognosis in glioma. METHODS: Expression of YAP1, p-YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 in 141 cases of low-grade gliomas (LGG) and 74 cases of high-grade gliomas (HGG) of surgical specimens were measured by immunohistochemistry. Pearson's X2 test was used to determine the correlation between immunohistochemical expressions and clinicopathological parameters. Pearson's or Spearman correlation test was used to determine the association between these proteins expression. Survival analysis was used to investigate the effect of these proteins on prognosis. RESULTS: High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in HGG compared with LGG (p=0.000). High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in 63.5%, 59.5%, 66.2% and 31.1% cases of HGG, respectively. YAP1 expression was associated to tumour location, Ki-67 and P53, STAT3 expression was related with Ki-67 and P53, and the expression of pSTAT3-S727 was associated with Ki-67. There was a significantly positive correlation between YAP1 and pSTAT3-S727 (p<0.0001; r=0.5663). Survival analysis revealed that patients with YAP1 and pSTAT3-S727 coexpression had worse overall survival (OS) and progression-free survival (PFS) (p<0.0001). Tumour grade, age, Ki-67 and YAP1 expression were independent prognostic factors for OS. In LGG group, both YAP1 and pSTAT3-S727 expressions were negative correlation with IDH1 mutation, YAP1 and pSTAT3-S727 coexpression showed worse OS and PFS of glioma patients. CONCLUSION: Our research showed that YAP1 and STAT3 were significantly activated in HGG compared with LGG. YAP1 significantly correlated with pSTAT3-S727 in glioma, YAP1 and pSTAT3-S727 coexpression may serve as a reliable prognostic biomarker and therapeutic target for glioma.

[Influence of Peripheral Blood Lymphocyte/Monocyte ratio (LMR) and Its Ratio to Lactate Dehydrogenase on Prognosis of Patients with Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To explore the influence of lymphocyte / monocyte ratio (LMR), LMR/lactate dehydrogenase (LDH) ratio on the prognosis of patients with diffuse large B-cell lymphoma. METHODS: Clinical data of 107 newly diagnosed patients with DLBCL, including age, sex, stage, B symptoms, IPI score, ECOG score, absolute lymphocyte count, absolute value of monocytes, the ratio of lymphocyte to monocyte(LMR), LDH, LMR/LDH, and SUVmax detected by FDG-PET/CT were analyzed. The best cut-off points of LMR and LMR/LDH were determined by receiver operating characteristics (ROC) curve; the chi-square test was used to analyze the correlation of clinical factors with LMR and LMR/LDH; Spearman correlation analysis was used to determine the correlation between serum LDH level and SUVmax; the Kaplan-Meier protocol was used to compare the overall survival (OS) rate and progression-free survival (PFS) rate between LMR and LMR/LDH groups; the Cox proportional risk model was used to carry out the multivariate analysis of prognostic factors. RESULTS: The optimal limit value for LMR and LMR/LDH (%) determined by ROC curve was 2.535 （P＜0.05） and 0.35% （P＜0.01） respectively. Patients with an LMR<2.535 had a higher incidence of advanced Ann Arbor stage, B symptoms, higher IPI score, higher ECOG score, and elevated LDH level, while patients with LMR/LDH 0.35% had the same trend as patients with LMR <2.535. A significant positive correlation between serum LDH and SUVmax was observed by Spearman correlation analysis (P<0.001). K-M survival analysis showed that the PFS rate and OS rate in high LMR group were significantly better than that in the low LMR group (P<0.05). K-M analysis showed that the PFS rate and OS rate in high LMR/LDH group were statistical significantly better than that in low LMR/LDH group (P<0.05). Multivariate COX analysis showed that the predictive value in LMR/LDH was much better than single LMR, which may be an independent prognostic factor for patients with DLBCL. CONCLUSION: At the initial diagnosis, high LMR/LDH suggests that DLBCL patient is a better prognosis.

Proteomics reveals protein phosphatase 1γ as a biomarker associated with Hippo signal pathway in glioma.

Hub proteins related with Hippo signal pathway in glioma were investigated using proteomics methods (Tandem Mass Tag, TMT) to determine the differentially expressed proteins in glioblastoma (GBM). Ingenuity Pathway Analysis (IPA) was performed to complement proteomic findings by identifying the top canonical pathways as well as to suggest novel proteins for the targeted therapy of glioma. A total of 222 formalin-fixed paraffin-embedded (FFPE) glioma tissue samples were used to verify the expression of protein phosphatase 1γ (PP1γ), Yes-associated protein 1 (YAP1), and SOX2 via immunohistochemistry. Bioinformatics analysis revealed these proteins as crucial in the Hippo signaling pathway in GBM. Spearman correlation was performed to analyze the relationship of these three proteins, and survival analysis was conducted to investigate their effects on prognosis. Among the 5808 proteins identified by TMT with the standard of P-value < 0.05 and fold change (FC) of>1.2 or <0.83, 1398 upregulated and 1060 downregulated differentially expressed proteins were found. IPA revealed that the Hippo signaling was activated in the top 10 canonical pathways, and PP1γ was activated in the Hippo signaling. Immunohistochemistry analysis indicated that PP1γ, YAP1, and SOX2 were highly and positively expressed in glioma. PP1γ expression was related to WHO grade (p = 0.003) and ki-67 expression (p = 0.012). Low PP1γ expression was associated with IDH1-mut in low-grade glioma (LGG; WHO grades II and III) (p = 0.037). PP1γ was positively correlated with YAP1 (p < 0.001; r = 0.259) and SOX2 (p = 0.009; r = 0.175). In survival analysis, age, WHO grade, ki-67 expression, and PP1γ expression independently predicted a short OS in total cohort (p < 0.05). Therefore, PP1γ is a hub protein associated with Hippo signal pathway in glioma, and its expression indicates poor prognosis in patients with glioma. Therefore, PP1γ may be a promising prognostic biomarker and a therapeutic target in glioma.

[Instability of Mitochondrial DNA D-loop Region Genes in Patients with Leukemia].

OBJECTIVE: To study the instability of mitochondrial DNA（mt DNA） D-loop region genes in patients with Leukemia. METHODS: The HV-1 and HV-2 regions of D-loop region in 24 patients with leukemia were amplificated and sequenced, then their results were compared with revised Cambridge reference sequence (rCRS) and Databank mtDB. The mutation rate was detected by SPSS 22.0 statistics software. RESULTS: The total mutation rate in patients was 95.83% (23/24), the detection showed 82 mutated genes, out of which 47 (57.32%) mutated genes located in HV-1 region, 35 (42.68%) mutated genes in HV-2 region. The comparison showed that the mutation rate in untreated (UT) group and treated (T) group of AML patients was (2.37±0.82)×10-3 and (4.76±2.45)×10-3 respectively(P＜0.01), the mutation rate in PR and CR groups of treated AML patients was (5.10±2.56)×10-3 and (4.51±2.51)×10-3 respectively (P＜0.05), the comparison among M3 group showed that the mutation rates in UT, PR and CR groups were (2.55±0.63)×10-3, (5.37±3.41)×10-3 and (3.71±1.65)×10-3 respectively (P＞0.05). CONCLUSION: The more high mutation rate and many kinds of mutation types exist in D-loop region, suggesting that the genes in D-loop region display the more strong instability, the chemotherapy may aggravate the instability of genes in D-loop region.

Anthracycline dose optimisation in patients with diffuse large B-cell lymphoma: a multicentre, phase 3, randomised, controlled trial.

BACKGROUND: Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. METHODS: In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology-Oncology Programs Evaluation System in China. Young patients (16-60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61-80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1-5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01852435. FINDINGS: From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6-77·6) and in the R-CEOP70 group was 72·4% ([66·5-77·5]; HR 1·00 [0·73-1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1-93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7-82·3]; 0·44 [0·25-0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4-83·7%]; 0·49 [0·27-0·86]; p=0·017). Grade 3-4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. INTERPRETATION: R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.

[Effect of DSA on Vascular Endothelial Cell Injury in NK Cell -Mediated ADCC].

OBJECTIVE: To investigate the injury effect of anti-donor specific antibody (DSA) on human umbilical vein enolothelial cells (HUVEC) in NK-mediated antibody-dependent cell cytotoxity (ADCC). METHODS: The peripheral blood of 10 healthy donors was colleced for allo-HSCT of AML patients diagnosed in Department of Hemology of the Tumor Hospital affiliated to Shanxi Medical University, then the peripheral blood NK cells were isolated and used as the effector cells; the HUVEC of passages 9-6 were selected and co-cultured with DSA, then the DSA-binding HUVEC were used as the target cells (CDH group), while the DSA-unbinding HUVEC were used as negative control (UDH group). After co-culture of effecor cells with target cells, the expression of IFN-γ was detected by flow cytometry and the HUVEC activity was detected by using MTT method, so as to indirectily reflect the injury effect of DSA-mediated ADCC on endothelial cells. RESULTS: With the increase of effector-target (E:T) ratio, the activity of HUVEC decreased, the expression level of IFN-γ increased. Under the some effector-target ratio (1∶1, 10∶1, 20∶1), the activity of HUVEC in CDH group was significantly lower than that of UDH group, and the expression of IFN-γ was significantly higher than that of the UDH group (P<0.05). CONCLUSION: DSA can damage vascular endothelial cells through the ADCC effect mediated by NK cells.

[T-Lymphoblastic Lymphoma Combined with Acute Myeloid Leukemia].

OBJECTIVE: To investigate the diagnosis and treatment of patients with T-lymphoblastic lymphoma（T-LBL）combined with acute myeloid leukemia（AML）. METHODS: The clinical features of 4 patients with T-LBL combined with AML were retrospectively analyzed, Among them the case 1 and 2 were synchronous occurrence，and case 3 and 4 were sequentially occurred. Especially for former 2 patients，the dliagnosis differentiated from the involved lymph node of AML is important. RESULTS: The biopsies, immunohistochemical（IHC）test and T-cell receptor（TCR）gene rearrangement of the lymph node have been re-evaluated in our institulion. The diagnosis of T-LBL was confirmed. The diagnosis of AML was based on morphology，cytochemistry，immunophenotypy，karyotype and fusion gene of cells. The biphenotypic and bilineal types were found by flow cytometriy（FCM）. The diagnosis of mixed acute leukemin（MAL）was confirmed. All the patients received chemotherapy，all of which died from leukemia. The survivnl duration was 2 to 5 months from the diagnosis of AML. CONCLUSION: T-LBL combined with AML is an aggressive disease with am unfarourable prognosis, The new therapies should be designed to treat these rare cases.

Three-year Follow-up on the Safety and Effectiveness of Rituximab Plus Chemotherapy as First-Line Treatment of Diffuse Large B-Cell Lymphoma and Follicular Lymphoma in Real-World Clinical Settings in China: A Prospective, Multicenter, Noninterventional Study.

BACKGROUND: Prospective real-life data on the safety and effectiveness of rituximab in Chinese patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) are limited. This real-world study aimed to evaluate long-term safety and effectiveness outcomes of rituximab plus chemotherapy (R-chemo) as first-line treatment in Chinese patients with DLBCL or FL. Hepatitis B virus (HBV) reactivation management was also investigated. METHODS: A prospective, multicenter, single-arm, noninterventional study of previously untreated CD20-positive DLBCL or FL patients receiving first-line R-chemo treatment at 24 centers in China was conducted between January 17, 2011 and October 31, 2016. Enrolled patients underwent safety and effectiveness assessments after the last rituximab dose and were followed up for 3 years. Effectiveness endpoints included progression-free survival (PFS) and overall survival (OS). Safety endpoints were adverse events (AEs), serious AEs, drug-related AEs, and AEs of special interest. We also reported data on the incidence of HBV reactivation. RESULTS: In total, 283 previously untreated CD20-positive DLBCL and 31 FL patients from 24 centers were enrolled. Three-year PFS was 59% (95% confidence interval [CI]: 50-67%) for DLBCL patients and 46% (95% CI: 20-69%) for FL patients. For DLBCL patients, multivariate analyses showed that PFS was not associated with international prognostic index, tumor maximum diameter, HBV infection status, or number of rituximab treatment cycles, and OS was only associated with age >60 years (P < 0.05). R-chemo was well tolerated. The incidence of HBV reactivation in hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/hepatitis B core antibody-positive patients was 13% (3/24) and 4% (3/69), respectively. CONCLUSIONS: R-chemo is effective and safe in real-world clinical practice as first-line treatment for DLBCL and FL in China, and that HBV reactivation during R-chemo is manageable with preventive measures and treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01340443; https://clinicaltrials.gov/ct2/show/NCT01340443.

G9A promotes gastric cancer metastasis by upregulating ITGB3 in a SET domain-independent manner.

Tumor metastasis is the leading cause of death in patients with advanced gastric cancer (GC). Limited therapeutic regimens are available for this condition, which is associated with a poor prognosis, and the mechanisms underlying tumor metastasis remain unclear. In the present study, increased histone methyltransferase G9A expression in GC tissues correlated with advanced stage and shorter overall survival, and in vitro and in vivo experiments revealed that G9A promoted tumor invasion and metastasis. Moreover, we observed that Reg IV induced G9A via the p-ERK/p-SP1 pathway. SP1 directly binds the G9A promoter and enhances G9A expression, and upregulated G9A then forms a transcriptional activator complex with P300 and GR, thereby promoting ITGB3 expression induced by dexamethasone (DEX) and contributing to GC metastasis. However, the G9A-mediated increase in ITGB3 expression was not dependent on the SET domain and methyltransferase activity of G9A. This study demonstrates that G9A is an independent prognostic marker and promotes metastasis in GC, thus suggesting that it may be a tumor biomarker and potential therapeutic target in GC.

Long noncoding RNA UCA1 promotes tumour metastasis by inducing GRK2 degradation in gastric cancer.

Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) regulate gene and protein expression by exerting an influence on transcriptional and post-transcriptional processes. Here, we report that the lncRNA UCA1 increases the metastatic ability of gastric cancer (GC) cells by regulating GRK2 protein stability by promoting Cbl-c-mediated GRK2 ubiquitination and degradation. This process then activates the ERK-MMP9 signalling pathway. Furthermore, we demonstrate that GRK2 is downregulated in GC cells and that silencing of GRK2 might cause similar phenotypic changes and signalling pathway activation as those induced by elevated UCA1 in GC cells. Our results suggest that UCA1 might function as a mediator of protein ubiquitination and may be a promising molecular target for GC therapy.