硼替佐米免疫应答调节机制的研究进展

硼替佐米是第一个蛋白酶体抑制剂,已被美国国家综合癌症网推荐用于多发性骨髓瘤、套细胞和外周T细胞淋巴瘤等多种血液系统肿瘤的治疗.研究发现,硼替佐米具有免疫调节作用,通过诱导免疫细胞凋亡、干扰免疫细胞膜分子的表达和分泌细胞因子等作用而影响机体的免疫应答.本文就硼替佐米对机体免疫应答的调节机制作一综述.     

硼替佐米免疫应答调节机制的研究进展

硼替佐米是第一个蛋白酶体抑制剂,已被美国国家综合癌症网推荐用于多发性骨髓瘤、套细胞和外周T细胞淋巴瘤等多种血液系统肿瘤的治疗.研究发现,硼替佐米具有免疫调节作用,通过诱导免疫细胞凋亡、干扰免疫细胞膜分子的表达和分泌细胞因子等作用而影响机体的免疫应答.本文就硼替佐米对机体免疫应答的调节机制作一综述.     

硼替佐米联合阿霉素诱导霍奇金淋巴瘤L428细胞凋亡的实验研究

硼替佐米是首个进行临床研究的蛋白酶体抑制剂,已应用于治疗多发性骨髓瘤(MM)及部分非霍奇金淋巴瘤,同时Mitsiades[1]和Ma等[2]体外实验证实硼替佐米与阿霉素联合处理MM细胞具有协同作用,而硼替佐米与阿霉素联合对霍奇金淋巴瘤(HL)有无协同作用未见报道.为研究硼替佐米对HL的抗肿瘤作用,我们观察了硼替佐米对HL细胞株L428细胞的增殖抑制作用,同时观察硼替佐米联合阿霉素对L428细胞的协同作用,并对其凋亡机制进行探讨.     

硼替佐米联合阿霉素诱导霍奇金淋巴瘤L428细胞凋亡的实验研究

硼替佐米是首个进行临床研究的蛋白酶体抑制剂,已应用于治疗多发性骨髓瘤(MM)及部分非霍奇金淋巴瘤,同时Mitsiades[1]和Ma等[2]体外实验证实硼替佐米与阿霉素联合处理MM细胞具有协同作用,而硼替佐米与阿霉素联合对霍奇金淋巴瘤(HL)有无协同作用未见报道.为研究硼替佐米对HL的抗肿瘤作用,我们观察了硼替佐米对HL细胞株L428细胞的增殖抑制作用,同时观察硼替佐米联合阿霉素对L428细胞的协同作用,并对其凋亡机制进行探讨.     

硼替佐米在移植物抗宿主疾病治疗中的作用

硼替佐米(bortezomib)属于一种蛋白酶体抑制剂,临床用于治疗复发性和难治性多发性骨髓瘤.目前,有关硼替佐米对肿瘤作用方面的研究已进入临床实验,但其在移植物抗宿主疾病中的作用尚处于动物模型实验阶段.本文就硼替佐米在移植物抗宿主疾病中对T细胞、树突细胞及细胞因子的作用作一综述.     

硼替佐米在移植物抗宿主疾病治疗中的作用

硼替佐米(bortezomib)属于一种蛋白酶体抑制剂,临床用于治疗复发性和难治性多发性骨髓瘤.目前,有关硼替佐米对肿瘤作用方面的研究已进入临床实验,但其在移植物抗宿主疾病中的作用尚处于动物模型实验阶段.本文就硼替佐米在移植物抗宿主疾病中对T细胞、树突细胞及细胞因子的作用作一综述.     

硼替佐米在移植物抗宿主疾病治疗中的作用

硼替佐米(bortezomib)属于一种蛋白酶体抑制剂,临床用于治疗复发性和难治性多发性骨髓瘤.目前,有关硼替佐米对肿瘤作用方面的研究已进入临床实验,但其在移植物抗宿主疾病中的作用尚处于动物模型实验阶段.本文就硼替佐米在移植物抗宿主疾病中对T细胞、树突细胞及细胞因子的作用作一综述.     

硼替佐米在移植物抗宿主疾病治疗中的作用

硼替佐米(bortezomib)属于一种蛋白酶体抑制剂,临床用于治疗复发性和难治性多发性骨髓瘤.目前,有关硼替佐米对肿瘤作用方面的研究已进入临床实验,但其在移植物抗宿主疾病中的作用尚处于动物模型实验阶段.本文就硼替佐米在移植物抗宿主疾病中对T细胞、树突细胞及细胞因子的作用作一综述.     

硼替佐米在移植物抗宿主疾病治疗中的作用

硼替佐米(bortezomib)属于一种蛋白酶体抑制剂,临床用于治疗复发性和难治性多发性骨髓瘤.目前,有关硼替佐米对肿瘤作用方面的研究已进入临床实验,但其在移植物抗宿主疾病中的作用尚处于动物模型实验阶段.本文就硼替佐米在移植物抗宿主疾病中对T细胞、树突细胞及细胞因子的作用作一综述.     

硼替佐米在移植物抗宿主疾病治疗中的作用

硼替佐米(bortezomib)属于一种蛋白酶体抑制剂,临床用于治疗复发性和难治性多发性骨髓瘤.目前,有关硼替佐米对肿瘤作用方面的研究已进入临床实验,但其在移植物抗宿主疾病中的作用尚处于动物模型实验阶段.本文就硼替佐米在移植物抗宿主疾病中对T细胞、树突细胞及细胞因子的作用作一综述.     

Molecular target drugs for malignant lymphoma

According to revised WHO classification for lymphoid malignancies, biological differences among pathological subtypes of lymphomas could be key points for molecular target therapies. For B cell lymphomas, CD20, CD22, CD19 can be molecules for target therapies, whereas there are not so many molecular targets in T cell lymphomas yet. However, novel molecular target drugs are developing from home and abroad. Especially, inhibitors for mTOR, IKK/JAK, HDAC, proteasome, HSP90, and proapoptotic molecules are developing in clinical trials for B cell- and T cell-lymphomas, and their anti-lymphoma activities will be considerably promising. Moreover, immunomodulatory drugs such as lenalidomide are also tried to investigate the effect on lymphomas. Here, some novel molecular drugs currently under development will be reviewed about their anti-lymphoma effects.     

原发性骨淋巴瘤1例及文献复习

目的:为加强对原发性骨恶性淋巴瘤(PLB)的临床诊断和治疗的认识,了解其临床表现的多样性、病因及预后,加深对其病理、影像学表现特点的认识,以期得到早期诊断及积极治疗以改善预后.方法:报道分析了一例以左小腿局部胀痛为首发症状的原发性骨恶性淋巴瘤,并复习国内外相关文献.结果:通过综合病史、临床及影像学检查、局部组织活检加病理可明确诊断.早期诊断及积极治疗可改善疾病的预后.结论:PLB是少见的结外淋巴瘤,以弥漫大B细胞性非霍奇金淋巴瘤多见,通常为溶骨性破坏,PLB病情发展迅速,局部症状重而全身症状轻,实验室检查及影像学表现无特异性,造成早期准确诊断非常困难,容易发生误诊,目前确诊主要依靠病理及免疫组化.应采取综合的临床诊断手段,加以鉴别诊断,尽早明确诊断,积极系统的治疗以改善预后.     

Ritonavir induces endoplasmic reticulum stress and sensitizes sarcoma cells toward bortezomib-induced apoptosis

The biosynthesis of immunoglobulin leads to constitutive endoplasmic reticulum (ER) stress in myeloma cells, which activates the unfolded protein response (UPR). The UPR promotes protein folding by chaperones and increases proteasomal degradation of misfolded protein. Excessive ER stress induces apoptosis and represents a molecular basis for the bortezomib sensitivity of myeloma. Most solid malignancies such as sarcoma, by contrast, are poorly bortezomib sensitive and display low levels of ER stress. We hypothesized that pharmacologic induction of ER stress might sensitize malignancies to bortezomib treatment. We show that the HIV protease inhibitor ritonavir induces ER stress in bortezomib-resistant sarcoma cells. Ritonavir triggered the UPR, decreased the degradation of newly synthesized protein, but did not directly inhibit proteasomal active sites in the therapeutic dose range in contrast to bortezomib. Whereas neither bortezomib nor ritonavir monotherapy translated into significant apoptosis at therapeutic drug levels, the combination strongly increased the level of ER stress and activated PERK, IRE1, and ATF6, synergistically induced CHOP, JNK, caspase-4, and caspase-9, and resulted in >90% apoptosis. In summary, ritonavir increases the level of ER stress induced by bortezomib, which sensitizes bortezomib-resistant cells to bortezomib-induced apoptosis. Ritonavir may therefore be tested clinically to improve the sensitivity of solid malignancies toward bortezomib treatment.     

Proteasome inhibition in hematologic malignancies

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non-Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.     

Proteasome inhibition in hematologic malignancies

Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade®), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non‐Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.     

Malignant lymphoma: REAL classification to new WHO classification

The Revised European-American Classification of Lymphoid Neoplasms(REAL) proposed in 1994 represented a new paradigm for the classification of lymphomas. This classification emphasized that each disease was a distinct entity, defined by a constellation of clinical and laboratory features, i.e., morphology and genetic features, immunophenotype, clinical presentation, and course. And it also noted that the site(s) of presentation were a signpost for important underlying biologic distinctions. A new WHO classification is planed to be proposed, re-categorizing entities of the REAL classification. Now, WHO members planed to publish the new classification as the bluebook of WHO at first in 1998 and now in 2000. This paper reports mainly different points in the new WHO classification of malignant lymphoma from the REAL classification.     

The results of histological and immunohistological studies of primary biopsies in 400 patients with non-Hodgkin's lymphoma in the North-West region of Russia (according to WHO classification)

AIM: To determine relative frequency of non-Hodgkin's lymphoma (NHL) variants according to WHO classification categories in the North-West of Russia by the data of the local pathomorphological department. MATERIAL AND METHODS: Four hundred consecutive untreated patients with NHL were diagnosed according to the WHO classification between January 2000 and October 2003 in the Regional Bureau of Pathology, St-Petersburg. The patients' age, gender, location of the biopsied tumor focus were considered. The immunohistochemical study was performed by the paraffin section-immunoperoxidase method. Cases of plasma cell myeloma and bone marrow trephine biopsy diagnosed neoplasms were excluded, the rest series of 377 cases was compared to other regional world series. RESULTS: B-cell lymphomas accounted for 79.6% and T-cell type for 20.4% of 377 NHL cases. 33.2% cases were different histological variants of diffuse large B-cell lymphoma, 17.0% were B-cell small lymphocytic lymphomas, 11.0%--follicular lymphomas, 4.5%--mantle cell lymphomas, 2.1%--extranodal marginal zone B-cell lymphomas (MALT-type), 1.9%--primary B-cell mediastinal lymphomas. Peripheral T-cell lymphomas, unspecified and anaplastic large T/null cell lymphomas were diagnosed in 6.4 and 4.2% of 377 cases, respectively. Other lymphoma diagnoses comprised 19.7%. CONCLUSION: Diffuse large B-cell lymphomas and B-cell small lymphocytic lymphomas are prevalent among B-cell neoplasms. Follicular lymphomas and mantle cell lymphomas are less common in the North-West of Russia compared to Europe and USA. The relative frequency of extranodal marginal zone B-cell lymphomas (MALT-type) is lower and anaplastic large T/null cell lymphomas is higher than these in International Lymphoma Study Group, Taiwan and Japan series. This study provides evidence that the distribution pattern of non-Hodgkin's lymphoma subtypes in the North-West of Russia shows significant differences with those from the rest of the world.     

免疫检查点抑制剂相关心肌炎分子机制研究进展

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）已成为目前应用最广的恶性肿瘤免疫疗法，主要包括CTLA-4（cytotoxic T lymphocyte associated antigen-4）抑制剂、PD-1/PD-L1（programmed death protein-1/ligand-1）抑制剂和LAG-3（lymphocyte activation gene-3）抑制剂。ICIs导致的最致命的免疫相关不良反应（immune-related adverse events, irAE）之一为免疫检查点抑制剂相关的心肌炎（immune checkpoint inhibitor-associated myocarditis, ICIAM）。ICIs联合治疗时ICIAM的发病率多高于单药治疗。其分子机制主要包括免疫检查点作为新抗原、肿瘤同源抗原的异位识别、免疫检查点心脏保护的阻断、自身抗体和炎症因子的产生以及微生物的调节作用等。目前已有多种治疗ICIAM药物及非药物性方案。对于ICIAM分子机制的探索和治疗管理方案的进步仍需多学科共同努力。     

370例恶性淋巴瘤的WHO(1997)分类

目的：研究恶性淋巴瘤的临床、病理特点。方法：根据WHO(1997)分类标准对370例恶性淋巴瘤患进行临床、病理及免疫表型分析。结果：非霍奇金淋巴瘤(NHL)359例，占97．03％；霍奇金淋巴瘤(HL)11例，占2．97％。NHL中，B细胞淋巴瘤246例，占68．52％；T细胞淋巴瘤108例，占30．08％；组织细胞性淋巴瘤和滤泡树突状细胞肉瘤各1例，NK细胞性淋巴瘤3例。结外淋巴瘤(196例，占54．6％)多于结内淋巴瘤(163例，占45．4％)。NHL中发病率较高的淋巴瘤类型依次为：弥漫大B细胞淋巴瘤(173例，占48．2％)，外周非特殊T细胞淋巴瘤(54例，占15．0％)，黏膜相关淋巴组织细胞淋巴瘤(31例，占8．6％)，NK／T细胞淋巴瘤(25例，占7.0％)，滤泡性淋巴瘤(21例，占5．8％)，间变性T细胞淋巴瘤(12例，占3．3％)。结论：应用WHO(1997)分类对恶性淋巴瘤进行分析研究，具有重要的临床意义。