沙利度胺与地塞米松联合治疗复发、难治性多发性骨髓瘤的疗效观察

目的观察沙利度胺(Thal)联合地塞米松(Dex)治疗复发、难治性多发性骨髓瘤的疗效。方法Tha l200mg/d,分早晚2次口服,持续2周;300mg/d,第3周,分早晚2次服用;400mg/d,第4～12周,分早晚2次口服。结果20例复发、难治性多发性骨髓瘤患者中,2例骨髓(BM)完全缓解(CR),CR率为10%,部分缓解(PR)4例,PR率为20%,骨髓未达PR及CR标准,但病情稳定,一般症状有所改善,此类患者所占比例为40%,无效6例,总有效率为70%。结论Thal联合Dex的方案是治疗复发、难治性多发性骨髓瘤的有效方案。     

NVF-DADMAC共聚物的水解反应研究

采用胶体滴定法研究了碱的质量分数对N-乙烯基甲酰胺-二甲基二烯丙基氯化铵共聚物(PNVF-DA)水解反应的影响,采用激光光散射仪测定了PNVF-DA水解产物(CPND)的重均分子量(MW)。结果表明:随着碱的质量分数的增加,CPND的胺化度也相应增大;当PNVF-DA中酰胺基与NaOH的摩尔比为1:4,在75℃下反应7h,其胺化度接近100%;胺化度为10%和20%的水解产物CPND-10和CPND-20的MW比未水解的PNVF-DA大,胺化度大于30%的CPND的MW递减。     

改良Hofmann法制备聚乙烯胺

采用Hofmann法制备聚乙烯胺(PVAm),考察了物料比、反应温度和加料方式等条件对聚乙烯胺收率和胺化度的影响,研究碱性反应母液的回收循环利用。结果表明,使用商品化非离子型聚丙烯酰胺(PAM)作为原料,可得到胺化度达84.54%的聚乙烯胺产品,回收的碱液可循环使用3次。反应采取将聚丙烯酰胺直接加入NaClO和NaOH溶液中制备聚丙烯酰胺氯胺化产物的加料操作方式,再加入碱溶液中进行重排反应,单位体积反应液中产品生产量可提高4倍。     

改良Hofmann法制备聚乙烯胺研究

本文研究采用Hofmann法制备聚乙烯胺（PVAm）技术,考察了物料比、反应温度和加料方式等条件对聚乙烯胺收率和氨化度的影响,研究碱性反应母液的回收循环利用。研究表明,使用商品化非离子型聚丙烯酰胺（PAM）作为原料,可得到胺化度达84.54%聚乙烯胺产品,回收的碱液可循环使用3次。反应采取将聚丙烯酰胺直接加入NaClO和NaOH溶液中制备聚丙烯酰胺氯胺化产物的加料操作方式,再加入碱溶液中进行重排反应,提高单位体积反应液中产品生产量。     

牛脂胺聚氧乙烯醚的合成与研究

以氢化牛脂基伯胺为起始剂,环氧乙烷为聚合单体,磷腈为催化剂,采用两步法合成了一种无气味、色度30的牛脂胺聚氧乙烯醚。该产品官能度为2,羟值70～180 mg/g,不饱和度0.02 mol/kg,分子量分布指数1.01,乙醛含量0.18 mg/kg。     

酚醛树脂关键参数对热压工艺成型磨具力学性能的影响

采用正交试验法研究了酚醛树脂关键参数中流动度（A）、中位径（B）和六亚甲基四胺质量分数（C）3个因素对热压工艺成型磨具力学性能的影响。正交试验结果表明：磨具力学性能受多项因素的影响,且存在显著的差异性;对磨具力学性能影响的主次因素顺序为六亚甲基四胺质量分数、流动度和中位径。在本研究范围内,酚醛树脂关键参数优选方案为六亚甲基四胺质量分数14%、流动度28 mm、中位径25μm。     

某天然气脱酸装置操作适应性分析研究

采用HYSYS模拟软件结合实际操作参数修正并验证后的模型,对某脱酸装置影响脱酸效果的原料气温度、胺液循环量、胺液浓度、吸收塔压力、闪蒸压力、再生塔回流比等主要因素进行了适应性分析及解释。结果表明:胺液循环量、贫胺液浓度、再生塔回流比是影响能耗的主要因素;原料气温度、吸收压力对吸收效果和性能影响有限;闪蒸压力的确定对再沸器负荷有一定的影响,应结合闪蒸气去向最终确定。可对该装置操作优化及指导后续操作优化。     

CO2混合胺吸收剂的研究进展

综述了近年来醇胺、烯胺两类混合胺吸收剂的研究进展,研究结果显示较为突出的混合胺吸收剂包括MEA＋AMP、MEA＋MDEA及MDEA＋PZ复合溶液;混合胺吸收剂是未来脱碳剂的研究热点,而离子液体作活化剂为混合胺吸收剂的研究提供了新的思路。     

度他雄胺的合成分析

本文对前列腺增生治疗药物度他雄胺的合成进行分析,其初始原料我们采用的是孕烯酮酸(3-羰基-4-雄甾-烯17β-羧酸),为非那甾胺中间体,制备过程中主要的步骤为:3-羰基-4-雄甾-烯17β-羧酸C-4,5位氧化开环;成环;还原氢化形成3-氧代-4-氮杂-5α-雄甾-17β-羧酸;继续对C-20位酰基胺化得到(5α,17β)-N-[2,5-双(三氟甲基)苯基]-3-氧代-4-氮杂雄甾-17-甲酰胺;最后进行C-1,2位氧化脱氢制得度他雄胺,总收率为30.0%。本文对合成过程中各个中间过程进行分析,找出最适宜的反应条件,从而更好的节约原料成本,增加产率。     

胺甲基聚丙烯酰胺的合成及其絮凝作用考察

在介绍合成高分子量聚丙烯酰胺(PAM)的同时,对PAM进行胺甲基改性。探讨了聚合温度、时间和二甲胺用量等因素对胺化度的影响。并对其絮凝效果进行考察。结果表明,胺甲基改性的阳离子型聚丙烯酰胺是一种絮凝效果好稳定性高,和沉降速度快的高分子絮凝剂。     

Bruton’s Tyrosine Kinase Targeting in Multiple Myeloma

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones’ hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton’s Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones’ interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.     

Tumor-Derived Small Extracellular Vesicles Induce Pro-Inflammatory Cytokine Expression and PD-L1 Regulation in M0 Macrophages via IL-6/STAT3 and TLR4 Signaling Pathways

Tumor-associated macrophages play a key role in promoting tumor progression by exerting an immunosuppressive phenotype associated with the expression of programmed cell death ligand 1 (PD-L1). It is well known that tumor-derived small extracellular vesicles (SEVs) affect the tumor microenvironment, influencing TAM behavior. The present study aimed to examine the effect of SEVs derived from colon cancer and multiple myeloma cells on macrophage functions. Non-polarized macrophages (M0) differentiated from THP-1 cells were co-cultured with SEVs derived from a colorectal cancer (CRC) cell line, SW480, and a multiple myeloma (MM) cell line, MM1.S. The expression of PD-L1, interleukin-6 (IL-6), and other inflammatory cytokines as well as of the underlying molecular mechanisms were evaluated. Our results indicate that SEVs can significantly upregulate the expressions of PD-L1 and IL-6 at both the mRNA and protein levels and can activate the STAT3 signaling pathway. Furthermore, we identified the TLR4/NF-kB pathway as a convergent mechanism for SEV-mediated PD-L1 expression. Overall, these preliminary data suggest that SEVs contribute to the formation of an immunosuppressive microenvironment.     

Reviewing the Significance of Vitamin D Substitution in Monoclonal Gammopathies

Vitamin D is a steroid hormone that is essential for bone mineral metabolism and it has several other effects in the body, including anti-cancer actions. Vitamin D causes a reduction in cell growth by interrupting the cell cycle. Moreover, the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, exerts various effects via its interaction with the vitamin D receptor on the innate and adaptive immune system, which could be relevant in the onset of tumors. Multiple myeloma is a treatable but incurable malignancy characterized by the growth of clonal plasma cells in protective niches in the bone marrow. In patients affected by multiple myeloma, vitamin D deficiency is commonly correlated with an advanced stage of the disease, greater risk of progression, the development of pathological fractures, and a worse prognosis. Changes in the vitamin D receptor often contribute to the occurrence and progress of deficiencies, which can be overcome by supplementation with vitamin D or analogues. However, in spite of the findings available in the literature, there is no clear standard of care and clinical practice varies. Further research is needed to better understand how vitamin D influences outcomes in patients with monoclonal gammopathies.     

人MNS_s血型系统抗N单克隆抗体的研制

应用杂交瘤技术,将 NS-1细胞与完整的红细胞免疫的 BALB/c 鼠脾细胞融合,获得MNS_s 血型系统分泌 IgG 抗 N 抗原的杂交瘤细胞株——10D_6。细胞培养上清效价1∶1024,亲和力7秒,经过8个月以上的连续传代培养,细胞增殖良好,性状稳定,持续分泌高效价,高亲和力,抗N 抗原的单克隆抗体。可作为血型检测的又一标准试剂。     

Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease.     

The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma

The development and effectiveness of novel therapies in multiple myeloma have been established in large clinical trials. However, multiple myeloma remains an incurable malignancy despite significant therapeutic advances. Accumulating data have elucidated our understanding of the genetic background of the malignant plasma cells along with the role of the bone marrow microenvironment. Currently, the interaction among myeloma cells and the components of the microenvironment are considered crucial in multiple myeloma pathogenesis. Adhesion molecules, cytokines and the extracellular matrix play a critical role in the interplay among genetically transformed clonal plasma cells and stromal cells, leading to the proliferation, progression and survival of myeloma cells. In this review, we provide an overview of the multifaceted role of the bone marrow microenvironment in the growth and development of malignant plasma cells in multiple myeloma.     

Deregulated Expression of Immune Checkpoints on Circulating CD4 T Cells May Complicate Clinical Outcome and Response to Treatment with Checkpoint Inhibitors in Multiple Myeloma Patients

Unlike solid-tumor patients, a disappointingly small subset of multiple myeloma (MM) patients treated with checkpoint inhibitors derive clinical benefits, suggesting differential participation of inhibitory receptors involved in the development of T-cell-mediated immunosuppression. In fact, T cells in MM patients have recently been shown to display features of immunosenescence and exhaustion involved in immune response inhibition. Therefore, we aimed to identify the dominant inhibitory pathway in MM patients to achieve its effective control by therapeutic interventions. By flow cytometry, we examined peripheral blood (PB) CD4 T cell characteristics assigned to senescence or exhaustion, considering PD-1, CTLA-4, and BTLA checkpoint expression, as well as secretory effector function, i.e., capacity for IFN-γ and IL-17 secretion. Analyses were performed in a total of 40 active myeloma patients (newly diagnosed and treated) and 20 healthy controls. At the single-cell level, we found a loss of studied checkpoints’ expression on MM CD4 T cells (both effector (Teff) and regulatory (Treg) cells) primarily at diagnosis; the checkpoint deficit in MM relapse was not significant. Nonetheless, PD-1 was the only checkpoint distributed on an increased proportion of T cells in all MM patients irrespective of disease phase, and its expression on CD4 Teff cells correlated with adverse clinical courses. Among patients, the relative defect in secretory effector function of CD4 T cells was more pronounced at myeloma relapse (as seen in declined Th1/Treg and Th17/Treg cell rates). Although the contribution of PD-1 to MM clinical outcomes is suggestive, our study clearly indicated that the inappropriate expression of immune checkpoints (associated with dysfunctionality of CD4 T cells and disease clinical phase) might be responsible for the sub-optimal clinical response to therapeutic checkpoint inhibitors in MM.     

Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL).     

The Significance of mRNA in the Biology of Multiple Myeloma and Its Clinical Implications

Multiple myeloma (MM) is a genetically complex disease that results from a multistep transformation of normal to malignant plasma cells in the bone marrow. However, the molecular mechanisms responsible for the initiation and heterogeneous evolution of MM remain largely unknown. A fundamental step needed to understand the oncogenesis of MM and its response to therapy is the identification of driver mutations. The introduction of gene expression profiling (GEP) in MM is an important step in elucidating the molecular heterogeneity of MM and its clinical relevance. Since some mutations in myeloma occur in non-coding regions, studies based on the analysis of mRNA provide more comprehensive information on the oncogenic pathways and mechanisms relevant to MM biology. In this review, we discuss the role of gene expression profiling in understanding the biology of multiple myeloma together with the clinical manifestation of the disease, as well as its impact on treatment decisions and future directions.     

幽门螺杆菌HpaA蛋白单克隆抗体的制备及其初步应用

目的 制备幽门螺杆菌(H.pylori)HpaA蛋白单克隆抗体,并检测其对H.pylori黏附胃腺癌细胞AGS的抑制作用。方法应用PCR法扩增HpaA基因,构建重组表达质粒pQE30-HpaA,表达并纯化重组HpaA蛋白;以其为抗原免疫BALB/c小鼠,将小鼠脾细胞与骨髓瘤细胞SP2/0融合,筛选阳性杂交瘤细胞株,采用间接ELISA和Western blot法检测单抗的特异性,间接ELISA检测细胞株培养上清和腹水抗体效价,并对其进行亚型鉴定和杂交瘤细胞株稳定性分析;扫描电镜观察重组HpaA蛋白单抗对H.pylori黏附AGS细胞的抑制作用。结果重组表达质粒pQE30-HpaA经双酶切、PCR及测序证明构建正确;表达的重组HpaA蛋白相对分子质量约为30 000,可溶性蛋白含量约占65%,纯化后纯度达85%以上;经细胞融合及筛选克隆获得了2株能稳定分泌抗HpaA单抗的杂交瘤细胞株,2株单抗与其他肠道细菌均无交叉反应,能与H.pylori全菌体发生特异性反应;乳胶凝集试验证明,该单抗属IgG3、κ型;2株单抗细胞培养液的抗体效价分别为1∶128～1∶256和1∶64～1∶128,腹水抗体效价分别可达1∶6 400～1∶12 800和1∶1 600～1∶3 200;杂交瘤细胞经反复冻存、复苏及多次传代,仍能稳定分泌高效价抗体;单抗可抑制H.pylori对AGS细胞的黏附作用。结论已成功制备了H.pylori HpaA蛋白单克隆抗体,为建立新的H.pylori现症感染诊疗方法奠定了基础。