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ObjectiveTo investigate the effect of Qiling Baitouweng Tang （QLBTWT） on proliferation and apoptosis， Janus kinase 2 （JAK2）/signal transducer and activator of transcription 3 （STAT3） signaling pathway and interleukin-10 （IL-10） in diffuse large B-cell lymphoma （DLBCL）. MethodWith human DLBCL cells OCI-LY10 and U2932 as research objects， cell proliferation was detected by cell counting kit-8 （CCK-8） assay. After treatment with 0， 4.6， 9.3， 18.7， 37.5， 75， 150 mg·L-1 QLBTWT for 24 h， the half-inhibitory concentration （IC50） of OCL-LY10 and U2932 cells was calculated to be 9.33， 16.13 mg·L-1， respectively， based on which， 9.5， 19， 38 mg·L-1 QLBTWT were selected for subsequent experiments. After 0， 9.5， 19， 38 mg·L-1 QLBTWT treatment for 24 h， the zymogen activities of Caspase-3， Caspase-8 and Caspase-9 in OCI-LY10 and U2932 cells were detected using corresponding activity assay kits （colorimetric）， and the IL-10 expression was detected by enzyme-linked immuno sorbent assay （ELISA）. The apoptosis rate and cell cycle of OCI-LY10 and U2932 cells treated with different concentrations of QLBTWT for 24 h were detected by flow cytometry. The expressions of apoptosis-related proteins ［B-cell lymphoma 2 （Bcl-2）， Bcl-2-associated X protein （Bax）， cleaved poly adenosine diphosphate ribose polymerase （cleaved PARP）， cleaved Caspase-3］， JAK2， STAT3， phospho-JAK2 （p-JAK2）， phospho-STAT3 （p-STAT3） pathway proteins， and c-Myc protein in OCL-LY10 and U2932 cells after 24 h treatment with 0， 9.5， 19， 38 mg·L-1 QLBTWT were all tested by Western blot. ResultAfter QLBTWT treatment on OCI-LY10 and U2932 cells for 24 h， cell proliferation was inhibited in each QLBTWT group compared with that in the control group （P<0.05， P<0.01）. The zymogens of Caspase-3， Caspase-8 and Caspase-9 were activated （P<0.01）， and there was an increase in cell apoptosis （P<0.05， P<0.01） and cell cycle arrest at Gap phase1 （G1） phase in 9.5， 19 and 38 mg·L-1 QLBTWT group （P<0.05， P<0.01）. After 9.5， 19 and 38 mg·L-1 QLBTWT treatment on OCI-LY10 and U2932 cells for 24 h， the expressions of Bcl-2， p-JAK2 and p-STAT3 proteins were decreased （P<0.01）， and the expressions of Bax， cleaved PARP and cleaved Caspase-3 proteins were increased （P<0.01）， but no significant change was observed in the expressions of JAK2 and STAT3 proteins. Compared with the conditions in the control group， the expressions of c-Myc， p-JAK2， and p-STAT3 proteins were down-regulated in 19 mg·L-1 QLBTWT group and 19 mg·L-1 QLBTWT+10 μg·L-1 IL-10 group （P<0.05， P<0.01）， and up-regulated in 10 μg·L-1 IL-10 group （P<0.05， P<0.01）， while there was no difference in JAK2/STAT3 proteins. ConclusionQLBTWT can inhibit proliferation and induce apoptosis of human DLBCL cells OCI-LY10 and U2932， and the potential mechanism may be related to the regulation of JAK2/STAT3 signaling pathway.
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ObjectiveTo assess the prognostic value of 18F-FDG PET/CT parameters for predicting therapeutic response in diffuse large B-cell lymphoma （DLBCL）. MethodsWe retrospectively analyzed the clinical data and 18F-FDG PET/CT radiomics features of 81 DLBCL patients enrolled between June 2015 and October 2020. Multivariate logistic regression analysis was used to identify the predictive factors for therapeutic response of DLBCL， based on which a predictive model was developed accordingly. The performance of the model was evaluated by receiver operating characteristic （ROC） curves and calibration plots. ResultsDuring the two years after first chemotherapy， 23 patients （28.3%） developed relapse and 58 patients （71.7%） had progression-free survival （PFS）. The analysis for the predictive capability of the binary logistic regression model incorporating the PET/CT features revealed that the imaging features of 18F-FDG PET/CT after chemotherapy were independent prognostic factors for PFS. Among them， SUVTHR-mean2 was the most important factor for predicting therapeutic response in DLBCL patients after chemotherapy， with a cutoff value of 2.00 （AUC=0.81）. Conclusions18F-FDG PET/CT showed a valuable prognostic performance for PFS in DLBCL patients after chemotherapy， with the imaging feature after chemotherapy SUVTLR-mean2 being the optimal independent predictor. Our predictive model of imaging features might have an important prognostic value in assessing the risk of disease progression， guiding the treatment and follow-up protocol， improving therapeutic efficiency and cutting down the medical cost.
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Subject(s)
Humans , Apoptosis , B-Lymphocytes , Blotting, Western , Carcinogenesis , Caspase 3 , Cell Line , Cell Proliferation , Curcumin , Immunoprecipitation , In Situ Hybridization , Lymphoma , Lymphoma, B-Cell , MicroRNAs , Real-Time Polymerase Chain Reaction , RNA , RNA, MessengerABSTRACT
@#[Abstract] Objective: To investigate the effect of histone demethylase JMJD3 (jumonji domain-containing protein 3) on the stemness of diffuse large B-cell lymphoma (DLBCL) cells. Methods: The relationship between the expression of JMJD3 and the overall survival of DLBCL patients was analyzed using the clinical data of DLBCL patients in TCGA database. The control plasmid (pCMV) and JMJD3 expression plasmid(pCMV-JMJD3)weretransfectedintoDLBCLcellsofABCandGCBsubtype via lipofectamine transfection. Then, the mRNAlevels of JMJD3,ALDH1, OCT4 and SOX2 were detected by RT-PCR and qPCR; the activity ofALDH1 enzyme was detected by Flow cytometry; the protein expressions of OCT4 and SOX2 were detected by Western blotting. Gene enrichment in DLBCL patients with high JMJD3 expression was analyzed by gene set enrichment analysis (GSEA). Results: The result of prognosis analysis showed that high expression of JMJD3 was related with poor prognosis in DLBCL patients (P<0.05); however, multivariate analysis showed that the expression of JMJD3 was not the independent factor affecting the prognosis of DLBCL patients (all P>0.05). The expression of JMJD3 was remarkably increased in DLBCL cells transfected with pCMV-JMJD3, which led to significantly increased mRNA level and enzyme activity of ALDH1 as well as up-regulated mRNA and protein expressions of OCT4 and SOX2 (P<0.05 or P<0.01). GSEA analysis showed that enrichment of Wnt/β-catenin signaling pathway related gene set was observed in DLBCL patients with high JMJD3 expression (P<0.05). Conclusion: JMJD3 promotes the stemness of DLBCL cells, which may be a potential therapeutic target for DLBCL patients.
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Objective: To investigate the prognostic value of prognostic nutritional index (PNI) in patients with diffuse large B-cell lym-phoma (DLBCL). Methods: We retrospectively reviewed the medical records of 82 patients with DLBCL treated at Tianjin Union Medi-cal Center between June 2010 and June 2016. The optimal cutoff value of PNI was determined using a receiver operating characteristic (ROC) curve and the Youden index. The relationship of high and low PNI with the clinical characteristics of the patients, therapeutic ef-ficacy, and prognosis were analyzed. Results: Overall, mean PNI of the patients was 46.17±8.8. When the PNI was 44.15, the Youden in-dex was found to be maximal, with a sensitivity of 74.6% and specificity of 67.2%. There were 38 patients (46.3%) in the low PNI group (<44.15) and 44 patients (53.7%) in the high PNI group (≥44.15). Data analysis showed that PNI was correlated with Eastern Coopera-tive Oncology Group performance status (ECOG PS), Ann Arbor stage, international prognostic index (IPI) score, and lactic acid dehydro-genase (LDH) level (P<0.05). The total effective rate of the low PNI group was significantly lower than that of the high PNI group (65.8% vs. 86.4%; χ2=4.848; P=0.028). The 3-year overall survival (OS) rate of the entire group of patients was 69.1%. The 1-, 2-, and 3-year OS rates of the low PNI group (86.8%, 67.8%, and 56.9%, respectively) were significantly lower than that of the high PNI group (96.7%, 89.5%, and 80.2%, respectively; χ2=9.421, P=0.002). Univariate analysis showed that PNI<44.15, ECOG PS≥2, IPI>2, stageⅢ/Ⅳ, and lymphocyte count<1.0×109/L had a significant impact on predicting OS (P<0.05). Multivariate analysis showed that PNI<44.15 (P=0.006) and stageⅢ/Ⅳ(P=0.011) were independent factors for predicting OS. Conclusions: PNI might be used as a simple and feasible clinical prognostic indicator in patients with DLBCL.
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Lymphoma is a group of heterogeneous hematological malignant tumors originating from lymph nodes or other lymphoid tissues, including Hodgkin's lymphoma and non-Hodgkin's lymphoma. Diffuse large B-cell lymphoma (DLBCL) is one of the most com-mon subtypes of non-Hodgkin's lymphoma (NHL) with obvious heterogeneity. Standard R-CHOP regimen (rituximab combined with cy-clophosphamide, adriamycin, vincristine and prednisone) can significantly improve the survival of more than 60% of patients. Howev-er, there are still about 30%-40% of patients with relapse or refractory disease, and the prognosis is very poor. How to prolong the sur-vival of relapsed/refractory DLBCL patients and improve their prognosis has become a research hotspot. With the continuous in-depth study of gene expression profiles and molecular mechanisms of drug resistance, new chemotherapy schemes and new drugs emerge, which brings new hope for individualized precise treatment of relapsed/refractory DLBCL. This article reviews the recent progress of targeted drugs in the treatment of relapsed/refractory DLBCL.
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Objective: To assess the clinical significance of changes in levels of serum β2 microglobulin (β2-MG), vascular endothelial growth factor (VEGF), and lactate dehydrogenase (LDH) in patients with diffuse large B-cell lymphoma (DLBCL) after treatment. Methods: A total of 89 patients with DLBCL who were admitted to the hospital between February 2015 an July 2017 were included in the DLBCL group and 40 normal, healthy persons admitted during the same period were selected as the control group. All DLBCL patients underwent standard chemotherapy after admission. Peripheral venous blood was collected before and after chemotherapy to determine any changes in serum β2-MG, VEGF, and LDH levels. Biomarker levels were also compared with those from normal, healthy subjects. The clinical and pathological data of all DLBCL patients were collected and the relationships between changes in biomarker levels, clinical and pathological parameters of DLBCL, and curative effects were analyzed. Results: The levels of serum β2-MG, VEGF, and LDH in the DLBCL group were higher than those in the control group (P<0.05) and all levels in DLBCL group decreased after chemotherapy (P<0.05). The effective rate of the R-CHOP group was higher than that of the CHOP group (P<0.05). Serum LDH levels were higher in patients with typical B symptoms than in those without such symptoms (P<0.05). Serum levels of β2-MG, VEGF, and LDH were higher in patients with Ann Arbor stageⅢ-Ⅳlymphoma, with bone marrow involvement, whose international prognostic index (IPI) was high-risk, and with treatment failure than in those with stageⅠ-Ⅱlymphoma, without bone marrow involvement, with low-risk IPI, and with treatment response (P<0.05). The levels of serum VEGF, β2-MG, and LDH were positively correlated with each other, and all three biomarkers were negatively correlated with treatment response (P<0.05). Conclusions: Levels of serum β2-MG, VEGF, and LDH are elevated in patients with DLBCL but are significantly decreased after treatment. Changes in expression levels of these three biomarkers are related to clinical stage, bone marrow involvement, IPI, and treatment response. These biomarkers can be used as a basis for monitoring DLBCL and evaluating curative effect and prognosis.
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Diffuse large B-cell lymphoma(DLBCL)is a highly invasive malignant lymphoma,and the molecular mechanism of its patho-genesis is not fully understood.Next generation sequencing(NGS)is an increasingly mature gene assay technology,which has been widely applied in recent years to study the genetics of DLBCL.Targeted therapy development has progressed significantly on the basis of these studies,which has made genetic mutations in DLBCL become the new research hotspot.This review summarizes the progress in research on progress-related gene mutations in DLBCL.
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@# Objective: To investigate the correlations between single nucleotide polymorphisms (SNPs) in the D-loop of mitochondrial DNA (mtDNA) and the disease risk as well as the prognosis of diffuse large B cell lymphoma (DLBCL). Methods: Blood samples from 108 DLBCL patients treated at the Department of Hematology of the Fourth Hospital of Heibei Medical University during July, 1991 and July 2012 were collected for this study; in addition, blood samples from 159 healthy controls during the same period were also collected. DNA was extracted according to the standard protocols for PCR amplification and SNP locus genotype analyses. The risk of D-loop SNPs was investigated by case-control study. Results: The minor alleles of nucleotides 73A/G, 263A/G, 315C/C insert were associated with a decreased risk for DLBCL. The minor allele of the nucleotides 200G/Awas associated with an increased risk for DLBCL. To further evaluate the predictive function of D-loop SNPs in DLBCL patients, five SNP sites were identified by Log-Rank test that with statistically significant prediction value of DLBCL survival in a univariate analysis. In a multivariate analysis, allele 16304 was identified as an independent predictor of DLBCL prognosis. The survival time of DLBCL patients with 16304C was significantly shorter than that of patients with 16304T (RR=0.513, 95% CI=0.266-0.989, P<0.05). Conclusion: The analysis of D-loop SNPs in mtDNA can help identifying the occurrence risks and poor prognosis subtypes of DLBCL.
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Non-Hodgkin lymphoma (NHL) is an adverse group of neoplasms that can occur at nodal and extranodal sites with varied prognosis. NHL involving soft tissue as a primary site accounts to 0.1% of cases and may mimic sarcoma; therefore, it is necessary to differentiate them as described by travis and co-authors, similarly. We describe a case of 72-year-old male patient with a mass in the right thigh. Magnetic resonance image reported a benign soft tissue tumour; fine-needle aspiration cytology suggested a soft tissue sarcoma and computed tomography imaging reported no other sites of involvement. PET (Positron emission tomography) scan done after first cycle of chemotherapy revealed enlarged right-side femoral and external iliac group of lymph nodes. On histological examination and immunohistochemistry, it was diagnosed as primary diffuse large B-cell lymphoma involving skeletal muscle. The case is presented to highlight the diagnostic difficulties due to its presentation on a rare site.
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Objective: We investigated the clinical significance and prognostic value of peripheral blood absolute lymphocyte count (ALC) in the diagnosis of diffuse large B-cell lymphoma. Methods:The medical records of 143 patients with diffuse large B-cell lymphoma were reviewed. These patients were diagnosed and underwent surgery in Tianjin Medical University Cancer Institute and Hospital, China, between February 2002 and April 2008. The correlation between different ALC levels and clinical features was statisti-cally analyzed. Results:Patients with low ALC (<1.0×109/L) at diagnosis showed B symptoms, an international prognostic index score of ≥2, advanced clinical stage (Ann Arbor III/IV), high lactate dehydrogenase level, and high β2-microglobulin level (P<0.05). Pa-tients with high ALC (≥1.0 × 109/L) responded well to treatment (P=0.003). In multivariate analysis, Ann Arbor stage and ALC level were independent prognostic factors of patients with diffuse large B-cell lymphoma. Patients with low ALC often exhibited advanced clinical stage (Ann ArborⅢ/Ⅳ). Conclusions:ALC level obtained at diagnosis is a novel, powerful prognostic factor of diffuse large B-cell lymphoma.
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Many predictive models have been proposed for better stratification of diffuse large B-cell lymphoma (DLBCL). Hans' algorithm has been widely used as standard to sub-classify DLBCL into germinal center B-cell (GCB) and non-GCB origins. However, there have been disagreements in the literature regarding its prognostic significance. Here, we retrospectively analyzed Hans' algorithm and the individual immunohistochemical biomarkers at different cut-off values (5%, 30%, 50% or 75%) in 94 Korean patients with DLBCL treated with combination chemotherapy with cyclophosphamide, daunorubicin, vincristine, and prednisone. No significant differences were observed between the GCB (18 patients, 19.1%) and non-GCB (76, 80.9%) groups. Among individual biomarkers, CD10 negativity (cut point: 30%) and bcl-6 positivity (cut point: 5%) were independent good prognostic markers in progression-free survival (PFS), whereas bcl-6 (cut point: 5%) positivity was an independent good prognostic marker in overall survival irrelevant of international prognostic index. The present study showed the lack of predictability of Hans' algorithm in DLBCL patients, and that CD10, Bcl-6 may have diverse prognostic significance at different cut-off values. Our results suggest that the proposed cut-off value may not be applied universally, and that the optimal cut-off value may need to be optimized for individual laboratory.