Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

CD14-CD10-CD45+HLA-DR-SSC+ neutrophils may be granulocytic myeloid-derived suppressor cell-like cells and relate to disease progression in non-Hodgkin's lymphoma patients.

We explored the frequency of CD14-CD10-CD45+HLA-DR-SSC++ neutrophils (CD10- neutrophils) in patients with non-Hodgkin's lymphoma (NHL), and their immunologic characteristics and clinical significance. Patients with NHL who were newly diagnosed (NDP; n = 33), in remission (RMP; n = 28) and relapsed (RLP; n = 29) were included, and 47 volunteers were recruited as healthy controls (HCs). The frequency of CD10- neutrophils in the peripheral blood from HC and patients with NHL was detected. CD10- and CD10+ neutrophils were sorted, and their cytology was analyzed. CD3+ T cells were also isolated and cultured with the autologous CD10- or CD10+ neutrophils, after which the proliferation and death rates of T cells were determined. The levels of arginase-1 (Arg-1) and reactive oxygen species (ROS) in CD10+ or CD10- neutrophils were examined. Few CD10- neutrophils were detected in HCs but were significantly elevated in patients with NHL, especially in NDP and RLP. In addition, CD10- neutrophils in NDP with advanced stage and high risk were markedly higher than those in NDP with limited stage and low risk. In RMP and RLP, the relapse-free survival and overall survival in patients with high CD10- neutrophils were shorter than those with low CD10- neutrophils. CD10- neutrophils from patients with NHL, which mainly consist of immature neutrophils, inhibit T-cell proliferation and facilitate T-cell death. Furthermore, a significant increase was observed in Arg-1 expression, along with an increase to a certain extent in ROS. CD10- neutrophils in patients with NHL have characteristics of myeloid-derived suppressor cells and may be related to disease progression and poor prognosis.

Predictive model for CAR-T cell therapy success in patients with relapsed/refractory B-cell acute lymphoblastic leukaemia.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in treating relapsed/refractory acute B-cell lymphoblastic leukaemia (R/R B-ALL). However, a subset of patients does not benefit from CAR-T therapy. Our study aims to identify predictive indicators and establish a model to evaluate the feasibility of CAR-T therapy. Fifty-five R/R B-ALL patients and 22 healthy donors were enrolled. Peripheral blood lymphocyte subsets were analysed using flow cytometry. Sensitivity, specificity, accuracy, positive and negative predictive values and receiver operating characteristic (ROC) areas under the curve (AUC) were determined to evaluate the predictive values of the indicators. We identified B lymphocyte, regulatory T cell (Treg) and peripheral blood minimal residual leukaemia cells (B-MRD) as indicators for predicting the success of CAR-T cell preparation with AUC 0.936, 0.857 and 0.914. Furthermore, a model based on CD3+ T count, CD4+ T/CD8+ T ratio, Treg and extramedullary diseases (EMD) was used to predict the response to CAR-T therapy with AUC of 0.938. Notably, a model based on CD4+ T/CD8+ T ratio, B, Treg and EMD were used in predicting the success of CAR-T therapy with AUC 0.966 [0.908-1.000], with specificity (92.59%) and sensitivity (91.67%). In the validated group, the predictive model predicted the success of CAR-T therapy with specificity (90.91%) and sensitivity (100%). We have identified several predictive indicators for CAR-T cell therapy success and a model has demonstrated robust predictive capacity for the success of CAR-T therapy. These results show great potential for guiding informed clinical decisions in the field of CAR-T cell therapy.

DNT cells mediate resistance to CAR-T cells therapy in a pediatric patient with relapsed and refractory B-ALL.

Chimeric antigen receptor T (CAR-T) cells therapy is a milestone achievement in the immunotherapy of relapsed and refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). However, some patients treated with CAR-T cells do not achieve complete remission, the mechanisms of which have not been elucidated. In the present study, we report a 9-year-old pediatric patient with refractory B-ALL received a triple infusion of autologous CD19 CAR-T cells therapy after the second relapse. CAR-T cells expanded in the peripheral blood and bone marrow. However, the patient did not achieve complete remission, indicating a lack of response to CAR-T cells therapy. Analysis of etiological factors revealed that the number of CD4 and CD8 double-negative T (DNT) cells was significantly upregulated in the peripheral blood, bone marrow, and autologous CAR-T cells products. In conclusiont, these findings indicate that DNT cells mediated resistance to CAR-T cells therapy in this pediatric patient with R/R B-ALL.

Lenalidomide treatment of isolated central nervous system relapse in acute lymphoblastic leukemia after HSCT and CAR-T cell therapy.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor T (CAR-T) cell are effective treatments for acute lymphoblastic leukemia (ALL). Various forms of intra- and extra-medullary relapses have been reported after HSCT and CAR-T cell therapy for ALL; however, no reports have investigated isolated central nervous system (CNS) relapse after HSCT and CAR-T cell therapy. Hence, no clinical treatment has been established for such rare patients. CASE PRESENTATION: An 18-year-old male patient with B cell ALL suffered from isolated CNS relapse after HSCT and CAR-T cell therapy. Conventional systemic intravenous and intrathecal chemotherapies were ineffective and intolerable. A unique immunosuppressive microenvironment of decreasing NK cell percentage and increasing IL-8 concentration and CAR-T cell exhaustion had been illustrated in the cerebrospinal fluid. Finally, the patient received immunomodulatory therapy with lenalidomide and obtained complete remission. CONCLUSION: Lenalidomide might be a therapeutic strategy for isolated CNS relapse after HSCT and CAR-T cell therapy.

Quartic CAR-T Cell Bridging to Twice Allo-HSCT Therapy in a Patient with Acute Lymphoblastic Leukemia.

Introduction: Chimeric antigen receptor T (CAR-T) cell therapy is an effective bridging treatment for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in relapsed or refractory acute lymphoblastic leukemia (ALL). However, repetitive CAR-T cell therapy and allo-HSCT can only be performed in a few patients because of technical difficulties and patients' physical, economic, and social conditions. Case Presentation: A 23-year-old female patient with second relapsed B-cell ALL (B-ALL) underwent human-murine chimeric CD19 CAR-T cell therapy twice, human-murine chimeric CD22 CAR-T cell therapy once, and humanized CD19 CAR-T cell therapy once. Moreover, she was sequentially bridged to her mother donor allo-HSCT once and cousin donor allo-HSCT once. Conclusion: Repetitive CAR-T cell therapy bridging to repetitive allo-HSCT is still a safe and active therapeutic strategy for patients with relapsed or refractory ALL.

Macroscopic Helical Assembly of One-Dimensional Coordination Polymers: Helicity Inversion Triggered by Solvent Isomerism.

Assembling macroscopic helices with controllable chirality and understanding their formation mechanism are highly desirable but challenging tasks for artificial systems, especially coordination polymers. Here, we utilize solvents as an effective tool to induce the formation of macroscopic helices of chiral coordination polymers (CPs) and manipulate their helical sense. We chose the Ni/R-,S-BrpempH2 system with a one-dimensional tubular structure, where R-,S-BrpempH2 stands for R-,S-(1-(4-bromophenyl)ethylaminomethylphosphonic acid). The morphology of the self-assemblies can be controlled by varying the cosolvent in water, resulting in the formation of twisted ribbons of R-,S-Ni(Brpemp)(H2O)·H2O (R-,S-2T) in pure H2O; needle-like crystals of R-,S-Ni(Brpemp)(H2O)2·1/3CH3CN (R-,S-1C) in 20 vol % CH3CN/H2O; nanofibers of R-,S-Ni(Brpemp)(H2O)·H2O (R-,S-3F) in 20-40 vol % methanol/H2O or ethanol/H2O; and superhelices of R-,S-Ni(Brpemp)(H2O)·H2O (R-,S-4H or 5H) in 40 vol % propanol/H2O. Interestingly, the helicity of the superhelix can be controlled by using a propanol isomer in water. For the Ni/R-BrpempH2 system, a left-handed superhelix of R-4H(M) was obtained in 40 vol % NPA/H2O, while a right-handed superhelix of R-5H(P) was isolated in 40 vol % IPA/H2O. These results were rationalized by theoretical calculations. Adsorption studies revealed the chiral recognition behavior of these compounds. This work may contribute to the development of chiral CPs with a macroscopic helical morphology and interesting functionalities.

Prognostic value of the WT-1 gene combined with recurrent cytogenetic genes in acute myeloid leukemia.

Wilms tumor gene 1 (WT-1 gene) is overexpressed in most patients with acute myeloid leukemia (AML) and is an indicator for minimal residual disease (MRD) monitoring, but because the WT-1 gene has relatively low specificity, further studies of the prognostic value of a combination of the WT-1 and other genes are needed. The aim of this study was to explore the prognostic value of the WT-1 gene combined with recurrent cytogenetic genes in AML. In AML, the transcript expression of the WT-1 gene was closely related to leukemic tumor burden and acted as an accurate molecular indicator for MRD detection. Most patients with low expression levels of the WT-1 gene after induction and consolidation therapy were significantly associated with favorable relapse-free survival (RFS) and overall survival (OS), but 17.6% of patients relapsed and died of primary disease. However, when analyzing the WT-1 gene combined with recurrent cytogenetic genes, none of the patients with low expression levels of the WT-1 gene and recurrent cytogenetic genes negative relapsed and died in the median follow-up time of 19 months (range: 3-94 months). Thus, the combination of the WT-1 gene and recurrent cytogenetic genes is a more accurate indicator for MRD monitoring and prognosis evaluation in AML patients.

Immune characteristics and prognostic implications of mucosal-associated invariant T cells in acute myeloid leukemia.

Increasing evidence suggests that mucosal-associated invariant T cells (MAITs) play a crucial role in anti-tumor responses against various cancers. In this study, we investigated the immune characteristics of MAIT cells in patients with acute myeloid leukemia (AML). Using multi-parameter flow cytometry, we performed phenotypic and functional analysis of MAITs in peripheral blood or bone marrow samples collected from 131 patients with AML including 99 newly diagnosed, 18 remission, and 14 relapsed cases, as well as 69 healthy controls. We found that MAITs exhibit signs of aging and exhaustion, particularly in CD8+ MAITs subset, at newly diagnosis. MAITs exhibit an effector memory or terminally differentiated phenotype. Frequency and number of MAITs reflect AML cell genetic features, tumor burden, disease status, and treatment responsiveness. Moreover, MAITs exhibit a highly activated or even exhausted state, as indicated by upregulation of PD-1. Furthermore, impaired production of Th1-type cytokines and increased secretion of Th17-type cytokines, granzyme B, and perforin were observed in MAITs from AML patients. Additionally, MAITs shifted toward producing cytokines that promote tumor progression, such as IL-8. Lower frequency of MAITs was associated with poorer overall survival (OS), and multivariate analysis revealed that MAITs frequency < 2.12% was an independent prognostic factor affecting OS. Collectively, our findings suggest that MAITs may play a role in immune deficiency in AML, emphasizing their potential importance in AML pathogenesis and treatment. These discoveries provide a theoretical basis for the development of novel immunotherapeutic strategies in AML.

Prognostic value of soluble programmed cell death ligand-1 (sPD-L1) in lymphoma: a systematic review and meta-analysis.

Previous studies on the prognostic value of soluble programmed cell death ligand 1 (sPD-L1) in lymphoma patients have yielded inconsistent results. Here, we conducted a meta-analysis and systematic review to investigate the prognostic significance of sPD-L1 in lymphoma, especially in diffuse large B-cell lymphoma (DLBCL) and NK/T-cell lymphoma (NK/TCL). A total of 11 studies with 1185 patients were included in the meta-analysis, and the combined results indicated that high sPD-L1 levels were associated with worse overall survival (OS) (HR = 2.27, 95%CI: 1.70-3.04) and progression-free survival (PFS) (HR = 2.68, 95%CI: 1.92-3.75). Furthermore, subgroup analysis showed that sPD-L1 remained a significant prognostic factor for OS. The meta-analysis indicated that sPD-L1 may be a potential prognostic biomarker for lymphoma, especially in DLBCL and NK/TCL, and high sPD-L1 levels were associated with worse survival prognosis.

Platelet is an unfavorable prognostic biomarker and associated with leukemia stem cells and immunomodulatory factors in acute myeloid leukemia.

Many clinical features, besides cytogenetic and molecular abnormalities, can affect the prognosis of the patients with acute myeloid leukemia (AML). Within this context it remains unclear if and how platelet counts affect the outcome of AML patients. In the present study, we examined the platelet counts at diagnosis in 633 newly diagnosed adult patients with AML from January 2010 to April 2021, and divided the cases into the group with low level of platelet counts (≤30×109/L, n=316) and high level of platelet counts (>30×109/L, n=317) according to the median platelet counts. We then validated the prognostic significance and potential mechanism of platelet counts on the relevance of spectral features for diagnostic risk stratification, initial induction therapy response, treatment effect maintenance, long-term survival, leukemia stem cells (LSCs) proportion, immunomodulatory cytokines level and immune cell subsets proportion. The results suggested that AML patients with a high level of platelet counts at diagnosis were associated with a high-risk molecular cytogenetic stratification, low complete remission (CR) rate, poor leukemia free survival (LFS), high proportion of LSCs, high level of transforming growth factor-ß (TGF-ß) and interleukin-1ß (IL-1ß), high proportion of regulatory T cells (Tregs) and monocytic myeloid-derived suppressor cells (M-MDSCs). It was demonstrated that platelet might be an unfavorable prognostic biomarker and was associated with LSCs and immunomodulatory cytokines as well as immune cell subsets in AML.

Palbociclib enhances the effect of doxorubicin-induced apoptosis in activated B-cell-like diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma around the world. While R-CHOP has significantly improved patient outcomes, a subset of patients still has poor outcome. Here, the oncogenic roles of cyclin dependent kinase 4/6 (CDK4/6)-Cyclin D (CCND) signaling axis in DLBCL and its potential mechanism were investigated to explore the possibility of targeting CDK4/6-CCND signaling axis for DLBCL therapy. The transcription levels, functional enrichment analysis, mutation analysis, and prognostic values were performed via the Oncomine, GEPIA, UALCAN, cBioPortal, and Metascape and GenomicScape databases. Expression of CDK4/6-CCND signaling axis in DLBCL patients and DLBCL cell lines was evaluated by qRT-PCR. Additionally, the impact of CDK4/6-CCND signaling axis on cell viability and apoptosis in DLBCL cell lines were evaluated in vitro . The transcription levels of CDK4/6-CCND signaling were increased in DLBCL patients. Meanwhile, in Gene Expression Omnibus dataset, the expression of CDK4 and CCND2 was higher in ABC-DLBCL, whereas the expression of CCND1 and CCND3 was higher in GCB-DLBCL. Moreover, according to the results of qRT-PCR, the expression of CDK4/6-CCND signaling axis in ABC-DLBCL cell line is higher than that in GCB-DLBCL cell lines. Prognostic analysis indicated that upregulation of CDK4, CCND2, and CCND3 was significantly associated with poor survival. Cell function experiments showed that palbociclib could enhance the apoptosis-promoting and cell viability-inhibiting effects of doxorubicin on ABC-DLBCL (SU-DHL-2) cells. Doxorubicin accumulation experiment showed that palbociclib promoted doxorubicin accumulation in ABC-DLBCL cells. Additionally, Western blot analysis demonstrated that palbociclib prevented antiapoptotic protein BCL2 expression in ABC-DLBCL cell line. Our study provides novel insights into targeted therapies for ABC-DLBCL patients.

Prognostic value of combined WT1 and multiparameter flow cytometry assessment for measurable residual disease after induction in non-APL acute myeloid leukemia.

The objective of this study was to investigate the expression pattern of Wilms tumor 1 (WT1) gene at diagnosis, complete remission (CR) and relapse status in non-acute promyelocytic leukemia (non-APL) acute myeloid leukemia (AML) patients, and further explore the prognostic value of measurable residual disease (MRD) assessment by WT1 gene and multiparameter flow cytometry (MFC). Our results showed that the average expression level of WT1 was 4026 ± 616.1 copies/104 ABL at diagnosis, 155.3 ± 36.03 copies/104 ABL at CR, and 1766 ± 238.8 copies/104 ABL at relapse, with statistically significant differences (p = .000). ROC analysis showed that WT1 expression levels were 118.1 copies/104 ABL and MFC-MRD was 0.155%, which had good predictive efficacy for relapse of patients during consolidation therapy. Both WT1-MRD and MFC-MRD had a significant impact on relapse-free survival (RFS) and overall survival (OS). Patients with WT1-MRD positive or MFC-MRD positive were associated with worse RFS (HR 3.840, 95% CI 1.582-9.320, p = .003), (HR 4.464, 95% CI 1.841-10.984, p = .001) and worse OS (HR 2.963, 95% CI 1.058-8.295, p = .039), (HR 3.590, 95% CI 1.254-10.280, p = .017). Besides, compared with patients who were negative for both WT1-MRD and MFC-MRD, patients who were positive both WT1-MRD and MFC-MRD were associated with worse RFS (HR 6.200, 95% CI 2.206-17.430, p = .001) and worse OS (HR 4.886, 95% CI 1.388-17.197, p = .013). This study demonstrates that combined assessment of MRD by WT1 and MFC improves relapse and prognosis prediction in non-APL AML patients, and may help guide interventions for disease relapse.

Idiopathic multicentric castleman's disease mimicking immunoglobulin G4-related disease responding well to Bortezomib: a case report.

BACKGROUND: Castleman's disease (CD) is a rare disease that has clinical and pathological similarities to lymphoma and is characterized by a high frequency of associated immunological dysfunction. ImmunoglobulinG4-related disease (IgG4-RD) is a collection of systemic disorders that affect numerous organs and are also referred to as IgG4-associated sclerosing diseases. CD and IgG4-RD are difficult to separate because they may manifest similar commin clinical features. CASE PRESENTATION: This case describes a 53-year-old female who, during routine medical check-up, exhibited a progressive increase in serum globulin levels and a simultaneous worsening of anemia symptoms, raising concern for a clonal plasma cell disease such as myeloma. However, bone marrow punctures did not reveal any abnormal plasma cells. Also, serum and urine immunofixation electrophoresis demonstrated no abnormal monoclonal protein bands. In addition, several laboratory findings excluded chronic liver disease, chronic infections caused by bacteria or viruses. Later, we found elevated serum IgG4 levels (10,700 mg/L), and identified multiple enlarged lymph nodes throughout the patient's body. Axillary lymph node aspiration revealed no abnormal lymphocytes, ruling out the possibility of lymphoma. Pathological morphology of the axillary lymph revealed a large number of plasma cells in the lymphatic follicles. In addition, there was a reduction in lymphatic follicle size and apoptosis of the germinal centres. Immunohistochemistry revealed IgG4+/IgG + in > 40% of cells, and more than 100 IgG4 + cells per high powered field (HPF) of specimen. As of now, finding strongly suggested IgG4-RD. This patient was treated with glucocorticoids and various immunosuppressive drugs, such as prednisone, cyclosporine, methotrexate, cyclophosphamide, mycophenolate mofetil, azathioprine and hydroxychloroquine. Unfortunately, the patient did not recover. Ultimately, idiopathic multicentric Castleman disease (iMCD) was diagnosed in relation to the patient's clinical presentation and laboratory tests, and after combination chemotherapy (VCD: Bortezomib, Cyclophosphamide and Dexamethasone), durable remission was achieved without serious adverse effects. During the follow-up period of one year and ten months, the patient remained stable. CONCLUSION: The diagnosis of Castleman must be distinguished from other disorders such as IgG4-RD, malignant lymphoma, reactive hyperplasia of various lymph nodes (mostly caused by viral infections), plasmacytoma, advanced HIV and rheumatic diseases. Besides observing systemic symptoms, laboratory tests such as immunoglobulin levels, complement levels, interleukin levels, and C-reactive protein levels should also be performed in order to determine a diagnosis.

CC chemokine receptor 2 (CCR2) expression promotes diffuse large B-Cell lymphoma survival and invasion.

In recent years, CC chemokine receptor 2 (CCR2) has been found to be involved in tumor growth, angiogenesis, epithelial mesenchymal transition, metastasis, and immune escape. CCR2 overexpression was first identified as a poor prognostic predictor in diffuse large B-cell lymphoma (DLBCL) in our published article, but the mechanisms involved remain unknown. In this work, we collected data from another 138 patients with DLBCL data and verified the CCR2 expression level and its relationship to clinicopathological characteristics. Furthermore, we explored the possible mechanisms via in vitro and in vivo experiments. We showed that CCR2 overexpression was an independent prognostic marker and predicted shorter overall survival (OS) and progression-free survival (PFS) in patients with DLBCL. Blockade of CCR2 expression with a CCR2 antagonist inhibited tumor cell proliferation, migration, and anti-apoptosis ability in vitro by affecting the PI3K/Akt signaling pathway and the p38 MAPK signaling pathway. Furthermore, administration of a CCR2 antagonist decreased tumor growth and dissemination of DLBCL cells and increased survival time in the xenograft model. Our study demonstrates that CCR2 expression plays an important role in the development of DLBCL by stimulating cell proliferation, migration, and anti-apoptosis. Therefore, the inhibition of CCR2 may be a potential target for anticancer therapy in DLBCL.

Down-regulation of BCL2L13 renders poor prognosis in clear cell and papillary renal cell carcinoma.

BACKGROUND: BCL2L13 belongs to the BCL2 super family, with its protein product exhibits capacity of apoptosis-mediating in diversified cell lines. Previous studies have shown that BCL2L13 has functional consequence in several tumor types, including ALL and GBM, however, its function in kidney cancer remains as yet unclearly. METHODS: Multiple web-based portals were employed to analyze the effect of BCL2L13 in kidney cancer using the data from TCGA database. Functional enrichment analysis and hubs of BCL2L13 co-expressed genes in clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) were carried out on Cytoscape. Evaluation of BCL2L13 protein level was accomplished through immunohistochemistry on paraffin embedded renal cancer tissue sections. Western blotting and flow cytometry were implemented to further analyze the pro-apoptotic function of BCL2L13 in ccRCC cell line 786-0. RESULTS: BCL2L13 expression is significantly decreased in ccRCC and pRCC patients, however, mutations and copy number alterations are rarely observed. The poor prognosis of ccRCC that derived from down-regulated BCL2L13 is independent of patients' gender or tumor grade. Furthermore, BCL2L13 only weakly correlates with the genes that mutated in kidney cancer or the genes that associated with inherited kidney cancer predisposing syndrome, while actively correlates with SLC25A4. As a downstream effector of BCL2L13 in its pro-apoptotic pathway, SLC25A4 is found as one of the hub genes that involved in the physiological function of BCL2L13 in kidney cancer tissues. CONCLUSIONS: Down-regulation of BCL2L13 renders poor prognosis in ccRCC and pRCC. This disadvantageous factor is independent of any well-known kidney cancer related genes, so BCL2L13 can be used as an effective indicator for prognostic evaluation of renal cell carcinoma.

Anti-CD19 CAR-T cell therapy bridge to HSCT decreases the relapse rate and improves the long-term survival of R/R B-ALL patients: a systematic review and meta-analysis.

Chimeric antigen receptor (CAR) T cell therapy improves the remission rate of refractory/relapsed B-acute lymphoblastic leukemia (R/R B-ALL) patients, but the relapse rate remains high. Recent studies suggest patients who underwent post-chimeric antigen receptor T cell therapy hematopoietic stem cell transplantation (post- HSCT) would achieve durable remission and better survival, but this remains controversial. To this end, we conducted a meta-analysis to assess the role of post-HSCT in R/R B-ALL. The Cochrane Library, Embase, and PubMed were used to identify relevant studies; the latest search update was on July 05, 2020. We used the Cochran Q test and I-squared statistics to test for heterogeneity among the studies analyzed. The fixed model and random model were used to combine results when appropriate. We performed all statistical analyses with Stata 12, and P < 0.05 was considered statistically significant. We included 18 studies with 758 patients in the meta-analysis. Our results indicated that post-HSCT was associated with lower relapse rate (RR: 0.40, 95% CI: 0.32-0.50, P = 0.000), better overall survival (HR: 0.37, 95% CI: 0.19-0.71, P = 0.003), better leukemia-free survival (HR: 0.20, 95% CI: 0.10-0.40, P = 0.000). However, post-HSCT did not influence OS in Caucasians, and CAR-T cells with CD28 co-stimulation factor bridged to HSCT did not influence OS. Post-HSCT decreased the relapse rate and improved the long-term survival of R/R B-ALL patients. R/R B-ALL patients would benefit from post-HSCT after CAR-T cell therapy.

Long non-coding RNA HOTAIR regulates myeloid differentiation through the upregulation of p21 via miR-17-5p in acute myeloid leukaemia.

Long non-coding RNA HOTAIR has been reported to play a key role in regulating various biological processes in various cancers. However, the roles and mechanisms of HOTAIR in acute myeloid leukaemia (AML) are still unclear and need to be investigated. In this study, we induced differentiation of four AML cell lines by all-trans retinoic acid (ATRA) and found HOTAIR was significantly upregulated in the process. Chromatin immunoprecipitation (ChIP) assays indicated that C/EBPß upregulated HOTAIR during ATRA induced differentiation in HL-60 cells. By gain- and loss-of-function analysis, we then observed that HOTAIR expression was positively correlated with ATRA-induced differentiation and negatively regulated G1 phase arrest in HL-60 cells. In addition, we found that HOTAIR promoted ATRA-induced differentiation via the regulation of the cell cycle regulator p21 via miR-17-5p. Moreover, we detected the expression of HOTAIR in 84 de novo AML patients, HOTAIR was found significantly downregulated in the AML patients compared to the iron deficiency anaemia (IDA) control group, negatively correlated with the platelet level in M2 patients. In all, our data suggest that HOTAIR may be subtype-specific in AML-M2 patients, also HOTAIR regulates AML differentiation by C/EBPBß/HOTAIR/miR-17-5p/p21 pathway. The findings of the present study provide a novel insight into the mechanism of lncRNA-mediated differentiation and indicate that HOTAIR may be a promising therapeutic target for leukaemia, especially for AML with M2 type.Abbreviation: AML: acute myeloid leukaemia; APL: acute promyelocytic leukaemia; ATRA: all-trans retinoic acid; CCK8: cell Counting Kit-8; CDKs: cyclin-dependent kinases ; CeRNA: competing endogenous RNAs; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; FAB: French-American-British; FCM: flow cytometry; HOTAIR: HOX transcript antisense RNA; IDA: iron-deficiency anemia; lncRNA: long non-coding RNA; 3'UTR: 3'untranslated region; MT: Mutation type; WT: Wild type; qRT-PCR: Quantitative real-time PCR.

Isolated Central Nervous System Blast Crisis of Chronic Myeloid Leukemia with Dasatinib Therapy.

BACKGROUND: Isolated central nervous system (CNS) blast crisis was uncommon in chronic myeloid leukemia (CML). METHODS: The present study reported an interesting case of a CML patient administered with dasatinib presenting with headache and seizure unconsciousness. Imaging investigation, immunophenotyping, bone marrow cytology inspection, chromosomal analysis, and polymerase chain reaction (PCR) were performed on a 41-year-old CML patient. RESULTS: Bone marrow examination revealed complete cytogenetic remission and there were no obvious abnormalities in head CT and MR. Cytomorphological examination of cerebrospinal fluid (CSF) showed 50% blasts. Flow cytometry analysis was showed 78.3% CSF cells expressing the specific myeloid antigens. PCR analysis on CSF cells was positive for BCR/ABL P210 fusion gene. All the above CSF findings were suggestive of CNS infiltrating isolated from bone marrow cytogenetic remission. CONCLUSIONS: Isolated CNS blast crisis of CML with dasatinib were rare. The mechanism still remains unclear and the treatment regimen requires further exploration. Flow cytometry showed great value to detect the blast cells in this patient.

Integrative analysis of hub genes and key pathway in two subtypes of diffuse large B-cell lymphoma by bioinformatics and basic experiments.

BACKGROUND: The germinal center B-cell (GCB) and activated B-cell (ABC) subtypes of diffuse large B-cell lymphoma (DLBCL) have a significant difference in prognosis. This study aimed to identify potential hub genes, and key pathways involved in them. METHODS: Databases including Gene Expression Omnibus (GEO), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING were accessed to obtain potential crucial genes and key pathways associated with the GCB and ABC. Then qRT-PCR and Western blot experiments were performed to verify the most clinically significant gene and pathway. RESULTS: Three cohort datasets from the GEO database were analyzed, including 195 GCB and 169 ABC samples. We identified 1113 differentially expressed genes (DEGs) between the GCB and ABC subtypes. The DEGs were mainly enriched in biological processes (BP). The KEGG analysis showed enrichment in cell cycle and Wnt signaling pathways. We selected the top 10 genes using the STRING database and Cytoscape software. We used 5 calculation methods of the cytoHubba plugin, and found 3 central genes (IL-10, CD44, CCND2). CCND2 was significantly related to the prognosis of DLBCL patients. Besides, our experimental results demonstrated a significantly higher expression of CCND2 in the ABC-type cell line than in the GCB-type; it was proportional to the expression of key proteins in the Wnt signaling pathway. CONCLUSION: CCND2 overexpression and Wnt pathway activation might be the main reasons for the poor prognosis of ABC-DLBCL.