Zuberitamab, an innovative anti-CD20 monoclonal antibody, for patients with primary immune thrombocytopenia in China: a randomized, double-blind, placebo-controlled, phase 2 study.

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease, and rituximab (RTX) induces long-term effect as second-line treatments. Zuberitamab is an innovative anti-CD20 monoclonal antibody, which was first developed in China and launched in diffuse large B lymphoma. This study aimed to investigate the safety, efficacy, and anticipated therapeutic dose of zuberitamab in Chinese ITP patients. Methods: This randomised, double-blind, placebo-controlled, phase 2 study was conducted at 26 hospitals in China. Eligible patients were aged 18-70 years, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous treatment and had a pre-treatment platelet count of <30 × 109/L. Patients randomly received zuberitamab in a dose escalation (100/300/600 mg) or placebo once-weekly for 4 weeks and followed up to 24 weeks. The primary endpoint is the proportion of patients with a platelet count ≥50 × 109/L at week 8. Secondary endpoints include the proportion of patients with platelet counts ≥50 × 109/L or ≥100 × 109/L at least once within week 12/24, the proportion of patients experiencing platelets increased twice more than baseline as well as ≥30 × 109/L at least once during the treatment. Adverse events, pharmacokinetic, B cell depletion and immunogenicity were also assessed. This study is registered with https://www.chictr.org.cn/as ChiCTR2100050513. Findings: From October 2021 to March 2023, 50 patients were screened for eligibility, of whom 32 patients were enrolled and randomly assigned to placebo (n = 4), zuberitamab 100 mg (n = 10), 300 mg (n = 8) and 600 mg (n = 10) groups. The primary endpoint (PLT ≥50 × 109/L at week 8) was achieved by 40% of patients in the 100 mg group, while none in the other groups. Within 12 weeks, the proportions of patients in each treatment group achieving at least one instance of platelet count ≥50 × 109/L or ≥100 × 109/L or an increase twice more than baseline as well as ≥30 × 109/L were (70%, 38%, 50%), (60%, 13%, 30%), and (80%, 50%, 70%) in zuberitamab 100/300/600 mg groups, respectively. By week 24, the proportions of patients achieving these secondary endpoints remained relatively stable or showed a mild increase of around 10%. The anticipated therapeutic dose of zuberitamab was 100 mg. The plasma concentration of zuberitamab showed an increasing trend with dose (100 mg-600 mg) and linear pharmacokinetic behavior. CD19+ B cells and CD20+ B lymphocytes rapidly declined to 0% within one week and consistently maintained reduced levels throughout the entire treatment phase in three groups. Adverse events occurred in all patients with most of them were mild to moderate, no severe infections occurred. A slight decrease in immunoglobulins was observed in the 600 mg group, but gradually recovered at week 20. Three patients (2 in 100 mg and 1 in 600 mg group) were tested positive for anti-zuberitamab antibodies. We also observed that women, disease duration <12 months, and MAIPA + patients may have higher response rates. Interpretation: This study preliminarily confirmed that 100 mg zuberitamab was safe and effective in treating ITP and was recommended to support further investigation. Funding: National Natural Science Foundation of China and Zhejiang Bioray Biopharmaceutical Co. Ltd.

Efficacy of chidamide maintenance therapy versus autologous stem cell transplantation versus observation as a post-remission choice in the survival of adult patients with peripheral T-cell lymphoma: Post hoc analysis of a prospective, multicenter, phase 2 study in China.

In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .

The Clinical Value of Systemic Immune Inflammation Index (SII) in Predicting the Severity of Hospitalized Children with Mycoplasma Pneumoniae Pneumonia: A Retrospective Study.

Objective: The Systemic Immune Inflammation Index (SII), as a novel inflammation biomarker that comprehensively reflects the inflammatory and immune status of the body, has not been reported in studies on Mycoplasma pneumoniae pneumonia (MPP) in children. This study aims to investigate whether SII can serve as an effective indicator for evaluating the condition of MPP. Methods: This study recruited a total of 304 hospitalized patients with mycoplasma pneumoniae pneumonia (MPP), including 78 patients with severe MPP (SMPP) and 226 patients with non-SMPP. Univariate analysis using chi-square test, t-test, and Mann-Whitney U-test was conducted to analyze the clinical data of the patients. Logistic regression analysis was employed to identify the main risk factors for SMPP. Receiver operating characteristic curves were plotted to evaluate the potential of using neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic immune response index (SIRI) to predict the severity of MPP. Results: The ROC curve results show that patients with SII values ≥ 699.00 are more likely to develop severe MPP (sensitivity=0.876, specificity=0.987, AUC=0.940), and the predictive value of SII is significantly better than that of NLR, PLR, and SIRI. The results of multivariate logistic regression analysis indicate that SII can serve as a major risk factor for distinguishing non-SMPP from SMPP. Conclusion: This study suggests that SII may be an effective indicator for predicting the severity of MPP in children. SII is more sensitive and specific than NLR, PLR, and SIRI in evaluating the condition of MPP.

[Functional mechanisms of WRKY transcription factors in regulating plant response to abiotic stresses].

WRKYs is a unique family of transcription factors (TFs) in plants, and belongs to the typical multifunctional regulator. It is involved in the regulation of multiple signaling pathways. This type of transcription factor is characterized to contain about 60 highly conservative amino acids as the WRKY domain, and usually also has the Cys2His2 or Cys2His-Cys zinc finger structure. WRKYs can directly bind to the W-box sequence ((T)(T) TGAC (C/T)) in the promoter region of the downstream target gene, and activate or inhibit the transcription of the target genes by interacting with the target protein. They may up-regulate the expression of stress-related genes through integrating signal pathways mediated by abscisic acid (ABA) and reactive oxygen species (ROS), thus playing a vital role in regulating plant response to abiotic stresses. This review summarizes the advances in research on the structure and classification, regulatory approach of WRKYs, and the molecular mechanisms of WRKYs involved in response to drought and salt stresses, and prospects future research directions, with the aim to provide a theoretical support for the genetic improvement of crop in response to abiotic stresses.

WWP2 binds to NKRF, enhances the NF-κB signaling, and promotes malignant phenotypes of acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is one of the hematological malignancies with a high recurrence rate. WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) is identified as a pivotal regulator of tumor progression. This study aimed to assess the possible role of WWP2 in AML. Analysis of the GEPIA database indicated an elevated WWP2 expression in AML. We established stable WWP2-overexpressed or WWP2-silenced cells using lentivirus loaded with cDNA encoding WWP2 mRNA or shRNA targeting WWP2. Notably, WWP2 overexpression facilitated cell proliferation and cell cycle progression, which was manifested as the increase of colony formation number, S-phase percentage and cell cycle related protein levels. As observed, WWP2 knockdown presented opposite effects, leading to inhibition of tumorigenicity. Strikingly, WWP2 knockdown induced apoptosis, accompanied by upregulation of pro-apoptosis proteins cleaved caspase-9, Bax and cleaved caspase-3 and downregulation of anti-apoptosis protein Bcl-2. Functionally, we further confirmed that WWP2 overexpression enhanced the NF-κB signaling and upregulated the levels of downstream genes, which may contribute to aggravating the development of AML. More importantly, by co-immunoprecipitation assay, we verified that WWP2 bound to NF-κB-repressing factor (NKRF) and promoted NKRF ubiquitylation. Dramatically, NKRF overexpression abolished the role of WWP2 in facilitating the process of AML. Overall, our observations confirm that WWP2 exerts a critical role in the tumorigenicity of AML, and NKRF is regarded as an essential factor in the WWP2-mediated AML progression. WWP2 may be proposed as a promising target of AML.

[Construction of a predictive model for performing bronchoalveolar lavage in children with Mycoplasma pneumoniae pneumonia and pulmonary consolidation]. / 存在肺实变的肺炎支原体肺炎患儿行支气管肺泡灌洗术的预测模型构建.

OBJECTIVES: To investigate the risk factors for performing bronchoalveolar lavage (BAL) in children with Mycoplasma pneumoniae pneumonia (MPP) and pulmonary consolidation, and to construct a predictive model for performing BAL in these children. METHODS: A retrospective analysis was performed for the clinical data of 202 children with MPP who were hospitalized in the Department of Pediatrics, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, from August 2019 to September 2022. According to whether BAL was performed, they were divided into BAL group with 100 children and non-BAL group with 102 children. A multivariate logistic regression analysis was used to identify the risk factors for performing BAL in MPP children with pulmonary consolidation. Rstudio software (R4.2.3) was used to establish a predictive model for performing BAL, and the receiver operator characteristic (ROC) curve, C-index, and calibration curve were used to assess the predictive performance of the model. RESULTS: The multivariate logistic regression analysis demonstrated that the fever duration, C-reactive protein levels, D-dimer levels, and presence of pleural effusion were risk factors for performing BAL in MPP children with pulmonary consolidation (P<0.05). A nomogram predictive model was established based on the results of the multivariate logistic regression analysis. In the training set, this model had an area under the ROC curve of 0.915 (95%CI: 0.827-0.938), with a sensitivity of 0.826 and a specificity of 0.875, while in the validation set, it had an area under the ROC curve of 0.983 (95%CI: 0.912-0.996), with a sensitivity of 0.879 and a specificity of 1.000. The Bootstrap-corrected C-index was 0.952 (95%CI: 0.901-0.986), and the calibration curve demonstrated good consistency between the predicted probability of the model and the actual probability of occurrence. CONCLUSIONS: The predictive model established in this study can be used to assess the likelihood of performing BAL in MPP children with pulmonary consolidation, based on factors such as fever duration, C-reactive protein levels, D-dimer levels, and the presence of pleural effusion. Additionally, the model demonstrates good predictive performance.

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.

Case report: A rare case of acute hemolysis in advanced rectal cancer after XELOX and nivolumab treatment: analysis of drug-dependent antibodies.

Objective: To investigate the mechanism, in vitro differential test and clinical significance of hemolytic anemia after receiving oxaliplatin and nivolumab treatment. Methods: We encountered a male patient with stage IV rectal cancer who experienced acute hemolysis during the ninth cycle of treatment with XELOX combined with nivolumab and cetuximab. The patient's blood samples were collected and tested for the presence of oxaliplatin or nivolumab antibodies on red blood cells. Results: Direct antiglobulin testing of red blood cells incubated with oxaliplatin was strongly positive, whereas cells incubated with nivolumab were negative, which suggested that oxaliplatin was responsible for the hemolysis. After short-term highdose glucocorticoid treatment, human normal immunoglobulin infusion, and other symptomatic treatments, the patient's condition rapidly improved, and he continued to receive nivolumab treatment without further hemolysis. Conclusion: Attention should be paid to the possibility of acute hemolysis when using oxaliplatin and nivolumab, and it is important to recognize and manage this adverse event early. We detected oxaliplatin-related antibodies on the surface of red blood cells in vitro, which provided evidence for the following treatments.

Electrospun PA6 multi-stage structured nanofiber membrane with high filtration performance for oily particles.

Oily particles pollution poses a tremendous threat to people's health, so it is urgent to develop air filtration materials with the ability of removing fine oily particles effectively. In this study, a nylon 6 multi-stage structured nanofiber membrane (PA6 MSNM) for effective air filtration of fine oily particles was designed and fabricated by adding a certain amount of tetrabutylammonium hexafluorophosphate (TBAHP) via one-step electrospinning. The PA6 MSNMs were composed of coarse trunk fibres and fine branching fibres. Benefiting from the properties of small pore size and high porosity, the resulting PA6 MSNMs exhibited high average filtration efficiency of 99.80% for oily aerosol particles of 0.20-4.59 µm, a low pressure drop of 251 Pa, and the high quality factor of 0.0248 Pa-1. More importantly, its filtration efficiencies for oily aerosol particles of 0.25 and 0.30 µm were up to 99.99% and 100.00%, respectively. It is expected that the multi-stage electrospun nanofiber membranes would have wide application prospects in air filtration, particularly for filtering oily particles.

Real-world treatment and outcome patterns of patients with mantle cell lymphoma in China: A large, multicenter retrospective analysis.

BACKGROUND: Mantle cell lymphoma (MCL) is an uncommon heterogeneous subtype of B cell non-Hodgkin lymphoma, and clinical features in MCL appear regional characteristics. MCL treatment opinions are not uniform between countries or regions within Asia and China, and Asian patient-specific data for MCL treatment are fewer. The study aims to explore the clinical characteristics, treatment patterns and prognosis of MCL patients in China. METHODS: A total of 805 patients diagnosed with MCL between April 1999 and December 2019 at 19 comprehensive hospitals in China were included in this retrospective analysis. Kaplan-Meier method coupled with the log-rank test was used for univariate analysis, and COX proportional hazards model was used for multivariate analysis (MVA). p < 0.05 was consided statistically significant. All outputs were produced using R version 4.1.0. RESULTS: The median age of the cohort was 60.0 years with a male-to-female ratio of 3.36:1. Five-year progression-free survival (PFS) and overall survival (OS) rates were 30.9% and 65.0%, respectively. High-intermediate/high-risk group according to MIPI-c, without high-dose cytarabine, lack of Auto-SCT as consolidation and maintenance treatment and SD/PD in initial treatment remained statistically relevant to poor PFS on MVA, and ki67 ≥50%, B symptoms, high-intermediate/high risk group according to MIPI-c, without high-dose cytarabine, lack of maintenance treatment, SD/PD in initial treatment and relapse/refractory state were independently associated with poorer OS on MVA. CONCLUSIONS: First-line high dose cytarabine exposure, auto-SCT as consolidation therapy obtained survival benefits in Chinese population. Our study further confirmed the value of maintenance treatment and explored the application of new drug treatment and bendamustine in R/R MCL patients.

The cross-talk of lung and heart complications in COVID-19: Endothelial cells dysfunction, thrombosis, and treatment.

The pandemic respiratory illness SARS-CoV-2 has increasingly been shown to be a systemic disease that can also have profound impacts on the cardiovascular system. Although associated cardiopulmonary sequelae can persist after infection, the link between viral infection and these complications remains unclear. There is now a recognized link between endothelial cell dysfunction and thrombosis. Its role in stimulating platelet activation and thrombotic inflammation has been widely reported. However, the procoagulant role of microparticles (MPs) in COVID-19 seems to have been neglected. As membrane vesicles released after cell injury or apoptosis, MPs exert procoagulant activity mainly by exposing phosphatidylserine (PS) on their lipid membranes. It can provide a catalytic surface for the assembly of the prothrombinase complex. Therefore, inhibiting PS externalization is a potential therapeutic strategy. In this paper, we describe the pathophysiological mechanism by which SARS-CoV-2 induces lung and heart complications through injury of endothelial cells, emphasizing the procoagulant effect of MPs and PS, and demonstrate the importance of early antithrombotic therapy. In addition, we will detail the mechanisms underlying hypoxia, another serious pulmonary complication related to SARS-CoV-2-induced endothelial cells injury and discuss the use of oxygen therapy. In the case of SARS-CoV-2 infection, virus invades endothelial cells through direct infection, hypoxia, imbalance of the RAAS, and cytokine storm. These factors cause endothelial cells to release MPs, form MPs storm, and eventually lead to thrombosis. This, in turn, accelerates hypoxia and cytokine storms, forming a positive feedback loop. Given the important role of thrombosis in the disease, early antithrombotic therapy is an important tool for COVID-19. It may maintain normal blood circulation, accelerating the clearance of viruses, waning the formation of MPs storm, and avoiding disease progression.

Efficacy and Safety of the Biosimilar IBI301 Plus Standard CHOP (I-CHOP) in Comparison With Rituximab Plus CHOP (R-CHOP) in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A Randomized, Double-Blind, Parallel-Group, Phase 3 Trial.

INTRODUCTION: Patients with diffuse large B-cell lymphoma (DLBCL) have limited access to rituximab. IBI301 is a recombinant chimeric murine/human anti-CD20 monoclonal antibody and is a candidate biosimilar to rituximab. This study aimed to assess the therapeutic equivalence of IBI301 and rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This multicenter, randomized, double-blind, parallel-group, phase 3 trial compared IBI301 and rituximab, both plus the chemotherapy of doxorubicin, cyclophosphamide, vindesine, and prednisone (CHOP), was conducted in 68 centers across China. Eligible patients with untreated CD20 positive (CD20+) DLBCL randomly received IBI301 (375 mg/m2) plus the standard CHOP or rituximab (375 mg/m2) plus the standard CHOP for six cycles of a 21-day cycle. The primary end point was the overall remission rate (ORR). Efficacy equivalence was defined if 95% CIs for the ORR difference between the two groups were within a ± 12.0% margin. RESULTS: Between August 22, 2016, and September 5, 2018, 419 patients were randomly allocated into the IBI301 group (N = 209) and rituximab group (N = 210). In the full analysis set, the ORR was 89.9% and 93.8% in the IBI301 and rituximab groups, respectively, and the ORR difference was -3.9% (95% CI - 9.1%-1.3%), falling within a ± 12.0% margin. The occurrences of treatment-emergent adverse events (TEAEs) (100% vs. 99.0%) and AEs of grade ≥ 3 (87.1% vs. 83.3%) were similar in the two groups (P > 0.05). CONCLUSIONS: IBI301 had a non-inferiority efficacy and a comparable safety compared with rituximab. IBI301 plus CHOP could be suggested as a candidate treatment regimen for untreated patients with CD20+ DLBCL. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov (NCT02867566).

The combination of chidamide with the CHOEP regimen in previously untreated patients with peripheral T-cell lymphoma: a prospective, multicenter, single arm, phase 1b/2 study.

OBJECTIVE: To assess the efficacy and safety of the novel histone deacetylase inhibitor, chidamide, in combination with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (Chi-CHOEP) for untreated peripheral T-cell lymphoma (PTCL). METHODS: A prospective, multicenter, single arm, phase 1b/2 study was conducted. A total of 128 patients with untreated PTCL (18-70 years of age) were enrolled between March 2016 and November 2019, and treated with up to 6 cycles with the Chi-CHOEP regimen. In the phase 1b study, 3 dose levels of chidamide were evaluated and the primary endpoint was determination of the maximum-tolerated dose and recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 study was 2-year progression-free survival (PFS). RESULTS: Fifteen patients were enrolled in the phase 1b study and the RP2D for chidamide was determined to be 20 mg, twice a week. A total of 113 patients were treated at the RP2D in the phase 2 study, and the overall response rate was 60.2%, with a complete response rate of 40.7%. At a median follow-up of 36 months, the median PFS was 10.7 months, with 1-, 2-, and 3-year PFS rates of 49.9%, 38.0%, and 32.8%, respectively. The Chi-CHOEP regimen was well-tolerated, with grade 3/4 neutropenia occurring in approximately two-thirds of the patients. No unexpected adverse events (AEs) were reported and the observed AEs were manageable. CONCLUSIONS: This large cohort phase 1b/2 study showed that Chi-CHOEP was well-tolerated with modest efficacy in previously untreated PTCL patients.

Sodium orthovanadate inhibits growth of acute leukemia HL60 cells and HL60/A cells in vitro.

Vanadium is an ultratrace element. The transition metal vanadium, widely exists in the environment and exhibits various biological and physiological effects in the human body, yet with no presently known specific physiological function in mammals. Sodium orthovanadate (SOV) is a kind of vanadium compound. SOV has shown promising antineoplastic activity in several human cancers. But the effects of SOV on acute promyelocytic leukemia (APL) are still unknown. In the present study, for the first time, we found that SOV could inhibit proliferation, induce G2/M cell cycle arrest and apoptosis, and could inhibit autophagy of acute leukemia cell lines in vitro. Thus, our findings suggest that SOV could effectively suppress the growth of acute leukemia HL60 cells and HL60/A cells through the regulations of proliferation, cell cycle, apoptosis and autophagy, and thus may act as a potential therapeutic agent in APL treatment.

A novel classification based on B-cell receptor signal gene expression correlates with prognosis in primary breast diffuse large B-cell lymphoma.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL), the most common histologic subtype of lymphoid malignancy in the breast, is a clinically and genetically heterogeneous disease that has insufficient systematic studies on the pathological and molecular features, optimal treatment scheme, as well as the prognostic factors. The aim of our study was to identify biomarkers and distinct subtypes of PB-DLBCLs and then evaluate the prognosis of this rare malignant lymphoma. We carried out hierarchical clustering analysis to evaluate protein expressions of potential biomarkers detected by immunohistochemistry staining of samples from 68 PB-DLBCL patients. The gene expression data from TCGA database was obtained to validate the identified clusters. We identified three robust clusters based on the B-cell receptor (BCR) signaling pathway, including two recognized NF-κB-dependent and PI3K-dependent clusters, and a distinct subset of PB-DLBCL with NF-κB-independent anti-apoptotic overexpression plus PI3K signaling, which exhibited an evolving definition and distinctive characters of a cluster group. Furthermore, survival analysis results showed an inferior outcome in NF-κB-dependent cluster patients and favorable survival in the PI3K-dependent cluster patients, suggesting an important predictive value of the three clusters. Our study provided a new perspective for understanding clinical complexity of PB-DLBCLs, and gave evidence for finding targeted biomarkers and strategies.

Epstein-Barr virus infection is associated with clinical characteristics and poor prognosis of multiple myeloma.

The aim of the present study was to evaluate the relationship of Epstein-Barr virus (EBV) infection and multiple myeloma (MM) and its impact on clinical characteristics and prognosis. Fresh peripheral blood mononuclear cells (PBMCs) from 139 MM patients who had been diagnosed and treated from January 2010 to May 2018 and 50 PBMC samples from healthy donors were obtained. PCR was carried out for detection of EBV-DNA. The results indicated a significantly higher EBV-DNA concentration among 139 MM patients compared with healthy controls (P<0.05). Correlation analysis showed that the expression of EBV-DNA was positively correlated with the serum free light chain ratio (sFLCR) and progressive disease (PD)/relapse (P<0.05). Especially, in EBV-DNA high-expression MM patients, EBV-DNA concentration for patients with sFLCR ≥100 was higher than that of patients with sFLCR <100. EBV-DNA concentration was higher in patients with disease PD/relapse than those without disease PD/relapse. In univariate analysis, the progress free survival (PFS) was inferior in MM patients with high expression of EBV-DNA, high lactate dehydrogenase (LDH), and high-risk according to mSMART and International Myeloma Working Group (IMWG), stage III according to R-ISS staging, extramedullary lesions, and genetic changes (P<0.05). However, in multivariate analysis, LDH, poor karyotype, R-ISS staging, and mSMART were independent prognostic factors for PFS. Taken together, our studies suggest that an association exists between EBV infection and clinical characteristics of MM patients, and EBV infection appears to have a slight impact on the prognosis of MM. However, the results require further validation in other independent prospective MM cohorts.

Role of miRNA-21 in the diagnosis and prediction of treatment efficacy of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) has a poor prognosis and requires early diagnosis and treatment. The aim of the present study was to investigate the difference between microRNA-21 (miRNA-21) expression in the plasma and cerebrospinal fluid (CSF) of patients with PCNSL, and to discuss the importance of miRNA-21 in its diagnostic and therapeutic evaluation. The research subjects were confirmed as patients with PCNSL with histopathological lesions at The First Affiliated Hospital of Harbin Medical University (Harbin, China) between December 2011 and 2017. Comparisons were drawn between the PCNSL, glioblastoma and the healthy control groups. CSF and plasma specimens were obtained from patients with PCNSL prior to chemotherapy, and CSF specimens were also obtained following chemotherapy. Plasma specimens were taken from patients with glioblastoma and the healthy control group. Using reverse transcription-quantitative polymerase chain reaction analysis, it was revealed that plasma miRNA-21 expression level had a notable diagnostic value in distinguishing PCNSL from glioblastoma, another common neurological tumor. Moreover, miRNA-21 expression levels in the plasma correlated positively with those in the CSF. Therefore, miRNA-21 in the plasma may be used as a novel diagnostic biomarker to distinguish patients with PCNSL from those with glioblastoma, whereas miRNA-21 in the CSF may have potential as a predictor of chemotherapeutic effect in PCNSL.

Salinomycin may inhibit the cancer stem-like populations with increased chemoradioresistance that nasopharyngeal cancer tumorspheres contain.

Tumor recurrence and metastasis of nasopharyngeal cancer (NPC) often result in the failure of treatment due to chemoradioresistance. Cancer stem cells (CSCs) have been observed to drive tumor initiation and tumor chemoradioresistance. Therefore, the poor prognosis of advanced NPC is likely to result from the failure to kill CSCs. Sphere formation may be used as an experimental method to enrich potential CSC subpopulations. At present, there are few reports on NPC tumorspheres. The present study focused on examining the cancer stem-like properties of NPC tumorspheres from NPC cell lines. Western blot analysis revealed that NPC tumorspheres had a higher expression of stem cell markers Nanog homeobox and SRY-box 2, compared with parental cells. It was additionally verified that NPC tumorspheres contained a high aldehyde dehydrogenase (ALDH) enzymatic activity compared with parental cells. ALDH+ cells were amplified by 9- to 10-fold in tumorspheres, compared with parental cells (1.8 vs. 16.9%). The tumorsphere cells exhibited an increased half maximal inhibitory concentration value of >10-fold with cisplatin compared with the control parental cells. Compared with the parental cells, the percentage of side population cells in the tumorsphere cell population increased significantly (10.3 vs. 2.3%; P<0.05). NPC tumorsphere cells demonstrated enhanced resistance to radiation. Further investigation verified that salinomycin inhibited NPC CSCs by selectively targeting its stem cells. Altogether, the data revealed that NPC tumorspheres contain cancer stem-like populations with increased chemoradioresistance. It was suggested that the serum-free culture of NPC cells may provide an appropriate model for researching the sensitivity of CSCs to therapeutic agents. It was additionally revealed that salinomycin is an efficient inhibitor of NPC CSCs, supporting the hypothesis that salinomycin may eliminate CSCs and imply a need for further clinical evaluation.

Radiation-resistant cancer stem-like cell properties are regulated by PTEN through the activity of nuclear ß-catenin in nasopharyngeal carcinoma.

Radiotherapy is the primary and most important treatment for nasopharyngeal carcinoma (NPC). Cancer stem-like cells (CSCs) have been shown to be resistant to radiation. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene has been suggested to play a role in stem cell self-renewal. In the present study, we sorted PTEN-/+ cells using a flow cytometer. The clone formation assay showed that PTEN- cells were more radioresistant than PTEN+ NPC cells. We found that PTEN- cells demonstrated a significant increase in tumorsphere formation and CSCs markers compared with PTEN+ cells. Silencing the expression of PTEN with siRNA resulted in increased expression of p-AKT, active ß-catenin and Nanog. siPTEN cells irradiated showed more radioresistant and DNA damage than parental cells. We also confirmed that down-regulation of ß-catenin expression with shRNA resulted in a reduced percentage of side population cells and expression of Nanog. shß-catenin cells significantly decreased survivin expression at 4 Gy irradiation in PTEN- cells compared with PTEN+ cells. In siPTEN cells, ß-catenin staining shifted from the cytoplasmic membrane to the nucleus. Furthermore, immunofluorescence showed that following irradiation of PTEN- cells, at 4 Gy, active ß-catenin was mainly found in the nucleus. Immunohistochemistry analysis also demonstrated that the PTEN-/p-AKT+/ß-catenin+/Nanog+ axis may indicate poor prognosis and radioresistance in clinical NPC specimens. Thus, our findings strongly suggest that PTEN- cells have CSCs properties that are resistant to radiation in NPC. PTEN exerts these effects through the downstream effector PI3K/AKT/ß-catenin/Nanog axis which depends on nuclear ß-catenin accumulation.

Causes and prognostic factors for early death in patients with acute promyelocytic leukemia treated with single-agent arsenic trioxide.

Early death (ED) is one of the most critical issues involved in the current care of patients with acute promyelocytic leukemia (APL). Factors identified as independent predictors of ED varied among published studies. We retrospectively analyzed the incidence, causes, and prognostic factors of ED in a series of 216 patients with newly diagnosed APL who received arsenic trioxide (ATO) as induction therapy. Multivariate logistic regression analysis was used to determine the association of clinical factors with overall ED, hemorrhagic ED, death within 7 days, and death within 8-30 days. In total, 35 EDs (16.2%) occurred that were caused by hemorrhage, differentiation syndrome (DS), infection, and other causes, in order of prevalence. The independent prognostic factors for overall ED and death within 8-30 days were the same and included serum creatinine level, Eastern Cooperative Oncology Group (ECOG) score, sex, and fibrinogen level. The risk factors for hemorrhagic ED and death within 7 days were similar and included serum creatinine level, ECOG score, and white blood cell count, while hemorrhagic ED was also associated with D-dimer. Our findings revealed a high rate of ED, and the causes of ED were similar to those among patients who received ATRA-based therapy. Increased creatinine level was the most powerful predictor, and an ECOG score greater than 2 was another strong prognostic factor for all four types of ED.