Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

PLAGL1 Is Identified as a Potential Diagnostic Marker for Co-Occurrence with Osteoporosis and Multiple Myeloma

Background: Osteoporosis (OP) is a common clinical manifestation of multiple myeloma (MM). The aim of this study was to investigate the possible molecular pathways and shared genes in the co-occurrence of OP and MM. Methods: The Gene Expression Omnibus database was used to retrieve gene expression information. Use WGCNA and differential analysis to screen out Hub genes. The GENEMANIA was used to build protein-protein interaction (PPI) networks. Enrichment analyses were performed to explore the functions. Validation datasets were selected to verify the diagnostic marker reliability of PLAGL1. The immune microenvironment of diseases was analyzed by immune infiltration analyses. Results: We confirmed a hub gene called PLAGL1, which is significantly under-expressed in both OP and MM. We found hub genes were associated with glucose and energy metabolism. Subsequently, the reliability of PLAGL1 for diagnosing OP and MM was verified using ROC curves, with all areas under the curve > 0.75. Moreover, PLAGL1 regulates t lymphocytes and may participate in the occurrence of OP in MM through immune pathways. Conclusions: PLAGL1 is a hub gene for the co-occurrence of OP and MM. It can regulate T-lymphocyte involvement in disease development. PLAGL1 may be a novel diagnostic marker for the co-occurrence of OP and MM.

Bcl-1 Rearrangement and Cyclin D1 Protein Expression in Multiple Myeloma Precursor Cells

The rearrangement of Bcl-1 gene (Bcl-1/IgH rearrangement) and expression of cyclin D1 in multiple myeloma (MM) precursor cells were studied and the role of cyclin D1 in the pathogenesis of MM was investigated. The BCL-1 rearrangement and cyclin D1 protein expression in 15 cases of MM were detected. By using hemi-nested polymerase chain reaction (PCR) the genomic DNA from fresh peripheral blood and bone marrow was amplified and the expression of cyclin D1 in the smears was detected by using immunohistochemical method. Ten volunteer with normal bone marrow served as control group. The results showed Bcl-1 rearrangement was detectable in 3/15 (20 %) MM patients and cyclin D, expression in 4/15 (27 % ) MM patients. BeLl-1 rearrangement and cyclin D1 protein expression were also detected in MM precursor cells. No overexpression of cyclin D1 or the rearrangement of the BeL-1 gene was found in the 10 volunteers. It was concluded that Bel-1 rearrangement and cyclin D1 protein overexpression were detected in MM precursor cells, speculating that overexpression of cyclin D1 protein may play an initial (critical) role in the pathogenesis of MM.

Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma

Objective:Myeloma bone disease(MBD)is the most common complication of multiple myeloma(MM).Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the severity of bone disease.However,the mechanism of C3 a/C4 a in osteoclasts MM patients remains unclear.Methods:The formation and function of osteoclasts were analyzed after adding C3 a/C4 a in vitro.RNA-seq analysis was used to screen the potential pathways affecting osteoclasts,and the results were verified by Western blot,q RT-PCR,and pathway inhibitors.Results:The osteoclast area per view induced by 1μg/m L(mean±SD:50.828±12.984%)and 10μg/m L(53.663±12.685%)of C3 a was significantly increased compared to the control group(0μg/m L)(34.635±8.916%)(P<0.001 and P<0.001,respectively).The relative m RNA expressions of genes,OSCAR/TRAP/RANKL/cathepsin K,induced by 1μg/m L(median:5.041,3.726,1.638,and 4.752,respectively)and 10μg/m L(median:5.140,3.702,2.250,and 5.172,respectively)of C3 a was significantly increased compared to the control group(median:3.137,2.004,0.573,and 2.257,respectively)(1μg/m L P=0.001,P=0.003,P<0.001,and P=0.008,respectively;10μg/m L:P<0.001,P=0.019,P<0.001,and P=0.002,respectively).The absorption areas of the osteoclast resorption pits per view induced by 1μg/m L(mean±SD:51.464±11.983%)and 10μg/m L(50.219±12.067%)of C3 a was also significantly increased(33.845±8.331%)(P<0.001 and P<0.001,respectively)compared to the control.There was no difference between the C4 a and control groups.RNA-seq analysis showed that C3 a promoted the proliferation of osteoclasts using the phosphoinositide 3-kinase(PI3 K)signaling pathway.The relative expressions of PIK3 CA/phosphoinositide dependent kinase-1(PDK1)/serum and glucocorticoid inducible protein kinases(SGK3)genes and PI3 K/PDK1/p-SGK3 protein in the C3 a group were significantly higher than in the control group.The activation role of C3 a in osteoclasts of MM patients was reduced by the SGK inhibitor(EMD638683).Conclusions:C3 a activated osteoclasts by regulating the PI3 K/PDK1/SGK3 pathways in MM patients,which was reduced using a SGK inhibitor.Overall,our results identified potential therapeutic targets and strategies for MBD patients。

Altered gene expression reveals molecular mechanisms underlying oridonin-induced apoptosis of multiple myeloma LP-1 cells

Objective： To investigate the effect of oridonin on proliferation and invasion of human multiple myeloma LP-1 ceils and the underlying mechanism. Methods： LP-1 cells in culture medium in vitro were treated with oridonin at the different concentration Cell proliferation was measured by Microwave Theory and Techniques （MTT） assay and cell apoptotic rate was detected by flow cytometry. Morphology of cell apoptosis was observed by transmission electron microscope. Expressions of Bax, Bcl-2, Caspase-3, NFqcB as well as I-~B mRNA were detected by real-time PCR. Results： The MTT assays and flow cytometry revealed that oridonin could inhibit the growth of LP-1 cells and cause apoptosis significantly; the suppression was both in time- and dose-dependent manner. Marked morphological changes of cell apoptosis were found under a transmission electron microscope after the cells were treated with oridonin at 25 ~rnol/L for 24 h. Along with the apoptotic process, Bcl-2, Caspase-3,NF-r,.B gene expressions were down-regulated （P〈0.05）. On the contrast, the Bax and I-~zB gene expressions were up-regulated （P〈0.05）. Conclusion： Oridonin could inhibit the proliferation of LP-1 cells via inducing apoptosis. We concluded that oridonin induces apoptosis in LP-1 cells via activation of caspase-3 as well as down-regulation of Bcl-2 and up-regulation of Bax expression. The results suggested that oridonin could induce apoptosis of LP-1 cells through mitochondria- and caspase3-dependent pathways. Meanwhile, the inhibition of NF-r,_B and the activation of I-~B indicate pro-apoptotic stimuli. In one word, oridonin might be an important potential anti-myeloma reagent.

IGIACP1 predicts the prognosis in multiple myeloma patients

Objective The aim of this study was to investigate the prognostic relevance of acid phosphatase 1(ACP1) expression in myeloma patients by using Gene Expression Omnibus(GEO) datasets.Methods A comprehensive search was performed in the GEO database in order to find appropriate datasets. The expression level of ACP1 was extracted from the dataset involving both newly diagnosed and relapsed myeloma patients, and a comparison was made. Clinical follow-up data and ACP1 expression were extracted, and survival analysis of overall survival was performed to compare the high-(top quartile) and low-expression(bottom quartile) groups. Analyses using Kaplan-Meier estimation, log-rank test, and restricted mean survival time(RMST) comparison were performed.Results The GSE 6477 dataset was used to make a comparison of the ACP1 expression levels among patients with newly diagnosed and relapsed myeloma. The ACP1 expression level was significantly higher in the relapsed group than in the newly diagnosed group [mean difference =-262.9, 95% confidence interval(CI) =(-420.2,-105.5), P = 0.002]. The GSE 2658 dataset was used for investigating the prognostic relevance of ACP1 expression in myeloma. The ACP1 high-expression group had a significantly worse prognosis [low vs high: hazard ratio = 0.54, 95% CI =(0.31, 0.95); χ2 = 5.02, log rank P = 0.0314]. The median survival was 55.9 months in the high-expression group and was not reached in the low-expression group. The restricted mean time loss(95% CI) was 11.03(12.97, 23.11) and 18.04(12.97, 23.11) for the low-and high-expression groups, respectively. The ratio of RMST(95% CI) between the two groups(high vs low) was 0.87(0.77, 0.99; P = 0.03).Conclusion Our study, for the first time, showed that ACP1 predicts the prognosis in multiple myeloma patients. Further studies are needed to determine the potential mechanism by which ACP1 is associated with clinical outcomes and should focus on the differential roles of low-molecular-weight protein tyrosine phosphatase(LMWPTP) isoforms.

The Role of 1q21 Gain on the Prognosis of Multiple Myeloma

Multiple myeloma(MM)is a clonal expansion of malignant plasma cells,and comprises approximately 10%of hematologic malignancies.Although various therapeutic agents and strategies,such as immunomodulatory agents,proteasome inhibitors,monoclonal antibodies and hematopoietic stem cell transplantation(HSCT)have been evaluated,MM remains largely incurable.It is therefore important to further explore the risk factors for disease progression,and to design trials aimed at improving the patient outcomes.Previous studies have considered the presence of a gain in 1q21 as a risk factor for a poorer overall survival.Gain of 1q21 is one of the most common chromosomal aberrations in MM,being detected by fluorescence in situ hybridization in 36%to 47%of newly-diagnosed patients,as well as 52%and 62%patients with relapsed MM.Although a series of reports identified 1q21 gain in MM as a significant and independent poor prognostic factor,other studies failed to demonstrate any prognostic value.Thus,the prognostic value of 1q21 gain in MM remains controversial.We reviewed the current knowledge about 1q21 gain and its value for the clinical management of MM.

多发性骨髓瘤患者的血清PINP、DKK1和SFRP3水平及其临床意义

目的探讨多发性骨髓瘤(MM)患者的血清I型原胶原氨基端前肽(PINP)、dickkopf Wnt信号通路抑制因子1(DKK1)和分泌型卷曲相关蛋白3(SFRP3)水平及其临床意义。方法纳入150例MM患者(MM组)及150健康体检者(对照组)。比较两组研究对象之间、不同临床分期MM患者之间、不同临床疗效MM患者之间的血清DKK1、PINP、SFRP3水平。采用Logistic回归模型分析治疗前血清DKK1、PINP和SFRP3水平与MM患者临床疗效的关系。采用受试者工作特征(ROC)曲线分析治疗前血清DKK1、PINP和SFRP3水平对MM患者临床疗效的预测效能。结果MM组患者治疗前血清DKK1、PINP和SFRP3水平高于对照组(P<0.05);Ⅰ期、Ⅱ期、Ⅲ期MM患者治疗前血清DKK1、PINP、SFRP3水平依次升高(P<0.05);有效组患者治疗前血清DKK1、PINP、SFRP3水平低于无效组(P<0.05)。治疗前血清DKK1、SFRP3、PINP水平升高是影响MM患者临床疗效的独立危险因素(P<0.05)。治疗前血清DKK1和SFRP3水平对MM患者临床疗效无预测价值(曲线下面积<0.5,P>0.05),而治疗前血清PINP水平对MM患者的临床疗效有一定的预测价值(曲线下面积=0.663,P<0.05)。结论MM患者治疗前的血清DKK1、PINP和SFRP3水平高于健康人群,且与疾病严重程度有关,是MM患者临床疗效的影响因素。治疗前血清PINP水平对预测MM患者的临床疗效有一定的价值。

Molecular Mechanisms Underlying the Time-dependent Autophagy and Apoptosis Induced by Nutrient Depletion in Multiple Myeloma:a Pilot Study

This study explored the molecular mechanisms underlying the time-dependent autophagy and apoptosis induced by nutrient depletion in human multiple myeloma cell line RPMI8226 cells.RT-PCR and qRT-PCR were used to evaluate the transcriptional levels of Deptor,JNK1,JNK2,JNK3,Raf-1,p53,p21 and NFκB1 at 0,6,12,18,24 and 48 h after nutrient depletion in RPMI8226 cells.We found that transcriptional levels of Deptor were increased time-dependently at 0,6,12 and 18 h,and then decreased.Its alternation was consistent with autophagy.Transcriptional levels of Raf-1,JNK1,JNK2,p53 and p21 were increased time-dependently at 0,6,12,18,24 and 48 h accompanying with the increase of apoptosis.Transcriptional levels of NFκB1 at 6,12,18,24 and 48 h were decreased as com-pared with 0 h.It was suggested that all the studied signaling molecules were involved in cellular re-sponse to nutrient depletion in RPMI8226 cells.Deptor contributed to autophagy in this process.Raf-1/JNK /p53/p21 pathway may be involved in apoptosis,and NFκB1 may play a possible role in in-hibiting apoptosis.It remained to be studied whether Deptor was involved in both autophagy and apoptosis.

髓细胞白血病1抑制剂在多发性骨髓瘤治疗中的研究进展

多发性骨髓瘤(MM)是一种不可治愈的B细胞恶性肿瘤,治疗方案包括化疗和自体干细胞移植。然而,目前药物在控制肿瘤进展和延长MM缓解时间方面作用有限,也并非所有患者都能够接受自体干细胞移植。多结构域B细胞淋巴瘤2(Bcl-2)家族蛋白,特别是髓细胞白血病1(MCL-1)的过度表达在MM的发病机制中起着关键作用。MCL-1过度表达与MM患者耐药和总体不良预后相关。因此,抑制MCL-1蛋白是杀死骨髓瘤细胞的一种治疗策略。在过去的十年中,选择性MCL-1抑制剂的开发取得了显著进展。现对MCL-1抑制剂在MM治疗中的研究进展进行介绍。

多发性骨髓瘤患者血清β2-MG、HMGB1水平与分期的相关性分析

目的:分析多发性骨髓瘤(multiple myeloma,MM)患者血清β2微球蛋白(β2-microglobulin,β2-MG)、高迁移率族蛋白B1(high mobility group protein B1,HMGB1)水平与分期的相关性。方法:回顾性分析2020年8月至2023年7月在平顶山市第一人民医院进行治疗的106例MM患者的临床资料,将其设为观察组,另选同期于本院体检中心体检健康的100例志愿者设为对照组,比较两组血清β2-MG、HMGB1水平,比较不同分期MM患者的血清β2-MG、HMGB1水平,采用Spearman相关系数分析MM患者临床分期与血清β2-MG、HMGB1水平的相关性,比较不同预后MM患者的血清β2-MG、HMGB1水平。结果:观察组血清β2-MG、HMGB1水平均高于对照组(P<0.05);Ⅰ期患者血清β2-MG、HMGB1水平低于Ⅱ期患者,Ⅱ期患者β2-MG、HMGB1水平低于Ⅲ期患者(P<0.05);相关性分析显示,MM患者临床分期与血清β2-MG、HMGB1水平呈正相关(P<0.05);完全缓解患者血清β2-MG、HMGB1水平低于部分缓解患者,部分缓解患者血清β2-MG、HMGB1水平低于复发患者(P<0.05)。结论:MM患者的血清β2-MG、HMGB1水平与其临床分期、预后关系密切,随着患者临床分期增加,其血清β2-MG、HMGB1水平随之升高,临床诊治时可结合以上指标判断患者病情进展,预测预后。

MUM-1、CD138、CD38对慢性子宫内膜炎的诊断价值及其与生殖预后的关系

目的分析多发性骨髓瘤癌基因-1(MUM-1)、白细胞分化抗原(CD)138、CD38在对慢性子宫内膜炎(CE)中的诊断价值及其与生殖预后的关系。方法选取2018年1月至2021年12月因不孕症于山东省济南市第二妇幼保健院生殖健康科就诊,并在山东大学齐鲁医院生殖医学中心接受体外受精-胚胎移植(IVF-ET)的194例患者作为研究对象。所有研究对象术前均接受宫腔镜检查,记录宫腔情况,取子宫内膜组织进行MUM-1、CD138、CD38标志物免疫组织化学染色及子宫内膜活检,并将子宫内膜苏木精-伊红染色法(HE)染色结果作为金标准,免疫组织化学染色结果与HE染色结果的一致性分析使用Kappa检验,分析免疫组织化学染色MUM-1、CD138、CD38单独及3项指标联合检测对CE的诊断效能。根据生殖预后将194例患者分为失败组和成功组,比较失败组和成功组的临床资料,采用多因素Logistic回归分析IVF-ET失败的危险因素。结果HE染色结果显示,194例接受IVF-ET的患者中90例确诊为CE;MUM-1、CD138、CD38单独及3项指标联合检测的免疫组织化学结果与HE染色结果的一致性分析显示,Kappa值分别为0.475、0.537、0.464、0.752(P<0.05);3项指标联合诊断CE的灵敏度、准确度、阳性预测值均高于MUM-1、CD138、CD38单独诊断,差异均有统计学意义(P<0.05);CD38单独诊断CE的灵敏度高于MUM-1、CD138单独诊断,特异度低于MUM-1、CD138单独诊断,差异均有统计学意义(P<0.05)。194例接受IVF-ET的患者中妊娠失败106例,妊娠成功88例。失败组与成功组年龄、体质量指数、不孕年限、月经经期、月经周期,以及基础内膜厚度、基础促卵泡刺激素、基础雌二醇、基础促黄体生成激素水平比较,差异均无统计学意义(P>0.05);失败组继发性不孕、人工流产次数≥1次、CE、MUM-1阳性、CD138阳性、CD38阳性患者比例均高于成功组,差异均有统计学意义(P<0.05)。多因素Logistic回归分析结果显示,继发性不孕、人工流产次数≥1次、患有CE、MUM-1阳性、CD138阳性、CD38阳性是IVF-ET失败的危险因素(P<0.05)。结论MUM-1、CD138、CD38联合检测可提升对CE的诊断效能,且患有CE、MUM-1阳性、CD138阳性、CD38阳性是IVF-ET失败的危险因素。

早期序贯治疗联合ASCT对中高危多发性骨髓瘤的临床疗效及对PD-1/PD-L1、T细胞和B细胞功能的影响

目的:分析早期序贯治疗联合自体造血干细胞移植(ASCT)对中高危多发性骨髓瘤的临床疗效及对PD-1/PD-L1、T细胞和B细胞功能的影响。方法:选择2019年1月—2022年5月南阳市中心医院收治的90例中高危多发性骨髓瘤患者作为研究对象,依照随机信封法分为观察组和对照组。对照组患者采用常规化疗方案进行治疗,观察组在对照组的基础上采用早期序贯治疗联合ASCT方案干预和治疗。干预治疗半年后对患者临床疗效进行评估,治疗前及治疗后半年时检测外周血中CD3^(+)T细胞、CD4^(+)T细胞、CD8^(+)T细胞、PD-1及PD-L1蛋白表达水平,检测受试者血清中T细胞相关细胞因子IFN-γ、TNF-α及B细胞相关抗体IgA、IgM和IgG水平情况。结果:观察组治疗临床疗效显著优于对照组,差异有统计学意义(χ^(2)=13.586,P<0.05);治疗后,两组患者血中CD3^(+)T细胞、CD4^(+)T细胞水平均显著升高,CD8^(+)T细胞水平显著降低,差异有统计学意义(t=7.299、2.521、12.629,P<0.05);治疗后,两组患者血清中PD-1及PD-L1蛋白均显著降低,差异有统计学意义(t=16.315、11.161,P<0.05);治疗后,两组患者血清中IFN-γ、TNF-α蛋白均显著升高,差异有统计学意义(t=30.046、32.084,P<0.05);治疗后,两组患者血清中IgA蛋白显著降低,IgM和IgG蛋白均显著升高,差异有统计学意义(t=47.013、50.959、27.694,P<0.05)。结论:联合早期序贯治疗联合ASCT对中高危多发性骨髓瘤患者干预可有效提高临床疗效,控PD-1及PD-L1水平,改善T细胞和B细胞功能。

多发性骨髓瘤肾功能不全患者血清PCPE1、IGFBP7水平及临床意义研究

目的分析多发性骨髓瘤(MM)肾功能不全患者血清前胶原C端蛋白酶增强子1(PCPE1)、胰岛素样生长因子结合蛋白7(IGFBP7)水平的变化,并探讨其临床意义。方法回顾性选取2019年2月至2021年2月苏州大学附属常熟医院收治的MM患者116例,检测患者血清PCPE1、IGFBP7水平和肾功能指标。根据患者肾功能分为肾功能不全组42例和肾功能正常组74例。比较两组患者肾功能指标和血清PCPE1、IGFBP7水平;分析MM肾功能不全患者血清PCPE1、IGFBP7水平与肾功能指标的相关性;分析MM患者肾功能不全的危险因素;分析血清PCPE1、IGFBP7对MM患者肾功能不全的预测效能。结果肾功能不全组患者血肌酐、血尿素氮、血尿酸、胱抑素C及血清PCPE1、IGFBP7水平均高于肾功能正常组(均P<0.05),估计的肾小球滤过率(eGFR)低于肾功能正常组(P<0.05)。MM肾功能不全患者血清PCPE1、IGFBP7水平与eGFR均呈负相关(均P<0.05),与血肌酐、血尿素氮、血尿酸及胱抑素C水平均呈正相关(均P<0.05)。高血清PCPE1水平、高血清IGFBP7水平均是MM患者发生肾功能不全的独立危险因素(均P<0.05)。ROC曲线分析显示,血清PCPE1、IGFBP7预测MM患者肾功能不全的AUC分别为0.833、0.806,最佳截断值分别为12.69、163.81μg/L,灵敏度分别为0.752、0.664,特异度分别为0.821、0.823,均有较高的预测效能;而血清PCPE1、IGFBP7联合预测MM患者肾功能不全的AUC高于单独指标预测(均P<0.05),预测效能更高。结论MM肾功能不全患者血清PCPE1、IGFBP7水平升高,且与肾功能不全程度有关,两者联合对MM患者肾功能不全有较高的预测效能。

程序性死亡蛋白1/程序性死亡蛋白配体1在初诊多发性骨髓瘤患者T淋巴细胞亚群的表达及临床意义

目的:探讨程序性死亡蛋白1(PD-1)/程序性死亡蛋白配体1(PD-L1)对初诊多发性骨髓瘤(MM)患者T淋巴细胞亚群的表达及其临床意义。方法:选取2021年12月—2022年12月锦州医科大学附属第一医院初诊为MM的44例患者作为试验组,另选取36例其他非肿瘤性疾病患者作为对照组。采集两组患者的骨髓标本,采用流式细胞术对有核细胞的CD8^(+)、CD4^(+)T细胞进行分离,检测PD-1与PD-L1的表达水平。收集试验组患者的临床资料,分析MM患者临床特征与CD4^(+)、CD8^(+)T细胞中PD-1、PD-L1的表达关系。结果:与对照组比较,试验组患者CD8^(+)、CD4^(+)T细胞水平升高,CD4^(+)/CD8^(+)水平降低,差异有统计学意义(P<0.05)。与对照组相比,试验组患者CD4^(+)、CD8^(+)T细胞中PD-1表达水平较高,PD-L1的表达水平较低,差异有统计学意义(P<0.05)。试验组患者的年龄、性别、mSMART 3.0风险、免疫分型、ISS分期、Durie-Salmon分期与CD4^(+)、CD8^(+)T细胞中PD-1、PD-L1的表达不存在显著差异(P>0.05)。结论:MM患者普遍存在着免疫功能失调,CD4^(+)、CD8^(+)T细胞中的PD-L1和PD-1与肿瘤细胞两者间的交互作用有着紧密联系。

Autocrine Production of Interleukin-6: A Mechanism of Interleukin-6 Independence in Dexamethasone-Resistant 7TD1 Murine Myeloma Cells

Several factors could contribute to proliferation of multiple myeloma (MM) cells independent of interleukin-6 (IL6) in the later stages of the disease. Our previous studies established a dexamethasone-resistant 7TD1 cell line (7TD1-Dxm) and have shown that one mechanism of resistance to dexamethasone is due to inhibition of cytochrome c release. We have also observed that 7TD1-Dxm cells proliferate independently of externally-added IL6. This study therefore aimed to elucidate the mechanisms responsible for IL6-independent proliferation in 7TD1-Dxm cells. Our results indicated that 7TD1-Dxm cells produced IL6 in an autocrine fashion. We have observed that dexamethasone-resistant 7TD1 cells become dexamethasone-resistant and IL6-independent for proliferation concomitantly. This strongly suggests that production of IL6 by 7TD1-Dxm cells may play an important role in the development of dexamethasone resistance. Consequently, further investigation of the molecular mechanisms responsible for IL6 production may be helpful in delineating the mechanisms leading to dexamethasone resistance.

内皮素-1在多发性骨髓瘤硼替佐米化疗中的意义及其与化疗敏感性和不良反应及免疫功能的相关性

目的探究内皮素-1(ET-1)在多发性骨髓瘤(MM)硼替佐米化疗中的意义及其与化疗敏感性和不良反应及免疫功能的相关性。方法选取2018年5月至2020年5月聊城市人民医院收治的110例复发难治MM患者作为研究对象,根据实体肿瘤疗效评价标准分为化疗应答组与化疗无应答组,每组55例。两组均接受硼替佐米化疗治疗,化疗前后均采用酶联免疫吸附测定法(ELISA)检测血清ET-1水平。比较两组化疗前后血清ET-1水平、免疫功能指标及不良反应发生情况,分析血清ET-1水平与化疗敏感性、不良反应发生情况、免疫功能的相关性。结果化疗后,两组血清ET-1水平均明显低于化疗前,差异有统计学意义(P<0.05);化疗应答组化疗前后血清ET-1水平均明显低于化疗无应答组,差异有统计学意义(P<0.05);化疗应答组胃肠道反应、周围神经病变及血液学不良反应发生率均明显低于化疗无应答组,差异有统计学意义(P<0.05);化疗后,两组CD4^(+)水平、CD4^(+)/CD8^(+)值及CD56^(+)自然杀伤细胞(NK)水平均明显高于化疗前,CD8^(+)水平均明显低于化疗前,且化疗应答组CD4^(+)水平、CD4^(+)/CD8^(+)值及CD56^(+)NK水平均明显高于化疗无应答组,CD8^(+)水平明显低于化疗无应答组,差异有统计学意义(P<0.05);化疗前后血清ET-1水平与硼替佐米化疗敏感性及免疫功能均呈负相关(r<0,P<0.05),与化疗不良反应发生率均呈正相关(r>0,P<0.05)。结论血清ET-1水平可作为评价复发难治MM患者硼替佐米化疗敏感性及化疗药物不良反应的特异性指标,对评估患者临床疗效及免疫功能具有积极意义。

红细胞沉降率、血清白蛋白及dickkopf WNT信号通路抑制剂1在多发性骨髓瘤中的表达及对预后的预测价值分析

目的探讨红细胞沉降率(ESR)、血清白蛋白(ALB)、dickkopf WNT信号通路抑制剂1(DKK1)在多发性骨髓瘤(MM)中的表达及对预后的预测价值。方法选取106例MM患者作为MM组,另选取同期100例健康体检者作为健康对照组,比较两组受试者ESR、ALB、DKK1水平。根据预后情况,将MM患者分为死亡组(n=14)和生存组(n=92),比较两组患者ESR、ALB、DKK1水平。采用受试者工作特征(ROC)曲线分析ESR、ALB、DKK1单独及联合检测对MM的诊断价值及对MM患者预后的预测价值。结果MM组患者ESR、DKK1均明显高于健康对照组,ALB明显低于健康对照组,差异均有统计学意义(P<0.01)。死亡组患者ESR、DKK1均明显高于生存组,ALB明显低于生存组,差异均有统计学意义(P<0.01)。ROC曲线显示,ESR、ALB、DKK1联合检测对MM的诊断价值及对MM患者预后的预测价值均高于任一指标单独检测。结论ESR、DKK1在MM中高表达,ALB在MM中低表达,ESR、ALB、DKK1联合检测对MM具有较好的诊断效能,可作为MM发生发展及预后判断的辅助参考指标,值得临床推广应用。

sBCMA、MCL-1与初治多发性骨髓瘤患者以硼替佐米为基础的化疗方案疗效的关系

目的探讨初治多发性骨髓瘤(MM)患者血清B细胞成熟抗原(sBCMA)、髓样细胞白血病蛋白-1(MCL-1)与以硼替佐米为基础化疗方案疗效的关系。方法选取该院2019年1月至2022年1月收治的83例初治MM患者作为研究对象。所有患者给予以硼替佐米为基础的化疗方案,按照疗效将其分为有效组及无效组。对比两组sBCMA及MCL-1水平及各项临床资料。采用多因素Logistic回归分析初治MM患者以硼替佐米为基础的化疗方案无效的影响因素,采用受试者工作特征(ROC)曲线分析sBCMA及MCL-1预测初治MM患者以硼替佐米为基础的化疗方案治疗无效的效能。结果有效60例,无效组23例。有效组sBCMA及MCL-1水平低于无效组,差异均有统计学意义(P<0.05);有效组国际分期系统(ISS)分期Ⅲ期比例[33.33%(20/60)]低于无效组[78.26%(18/23)],差异有统计学意义(P<0.05)。多因素Logistic回归分析发现,sBCMA及MCL-1水平升高、ISS分期Ⅲ期均是初治MM患者以硼替佐米为基础的化疗方案治疗无效的危险因素(P<0.05)。sBCMA及MCL-1单独预测初治MM患者以硼替佐米为基础的化疗方案治疗无效的曲线下面积(AUC)分别为0.751(95%CI:0.711~0.820)、0.766(95%CI:0.709~0.835),2项指标联合检测的AUC为0.895(95%CI:0.811~0.978)。结论初治MM患者sBCMA、MCL-1水平及ISS分期与以硼替佐米为基础的化疗方案疗效有关,可能成为预测初治MM患者对以硼替佐米为基础化疗方案疗效的辅助指标,且2项指标联合预测效能更高。

Wilms瘤基因1、B7家族成员H3及自然杀伤细胞表面受体在多发性骨髓瘤和淋巴瘤中的表达及临床意义

目的探讨Wilms瘤基因1(WT1)、B7家族成员H3(B7H3)及自然杀伤(NK)细胞表面受体在多发性骨髓瘤和淋巴瘤中的表达及临床意义。方法选取56例多发性骨髓瘤患者和50例淋巴瘤患者,分别作为骨髓瘤组和淋巴瘤组,采用流式细胞仪检测两组患者NK细胞占有核细胞比例,采用荧光定量聚合酶链反应(PCR)检测两组患者WT1、B7H3 mRNA相对表达量以及NK细胞表面受体NKG2D、CD69、程序性死亡受体1(PD-1)mRNA的相对表达量。随访1年,比较不同预后情况多发性骨髓瘤和淋巴瘤患者WT1、B7H3 mRNA相对表达量及NK细胞占有核细胞比例。绘制受试者工作特征(ROC)曲线,计算曲线下面积(AUC),评估各指标对多发性骨髓瘤患者和淋巴瘤患者预后的预测价值。结果骨髓瘤组患者B7H3 mRNA相对表达量低于淋巴瘤组,PD-1、NKG2D mRNA相对表达量及NK细胞占有核细胞比例均高于淋巴瘤组,差异均有统计学意义(P﹤0.05)。随访结束,56例多发性骨髓瘤患者中,预后不良15例,预后良好41例,预后良好的多发性骨髓瘤患者B7H3 mRNA相对表达量明显低于预后不良患者,差异有统计学意义(P﹤0.01)。B7H3预测多发性骨髓瘤患者预后的AUC为0.748(95%CI:0.605~0.891),cut-off值为3.29,此时的灵敏度为0.867,特异度为0.659。随访结束,淋巴瘤组患者中,预后不良19例,预后良好31例,预后良好淋巴瘤患者B7H3 mRNA相对表达量低于预后不良患者,NK细胞占有核细胞比例高于预后不良患者,差异均有统计学意义(P﹤0.05)。B7H3、NK细胞占有核细胞比例联合检测预测淋巴瘤患者预后的AUC为0.852(95%CI:0.731~0.973),灵敏度为0.871,特异度为0.737。结论B7H3及NK细胞受体在多发性骨髓瘤和淋巴瘤患者中的表达水平存在差异,但WT1水平的差异不明显,B7H3及NK细胞占有核细胞比例对多发性骨髓瘤及淋巴瘤患者的预后有一定的预测意义。