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991.
Ciavarella S Grisendi G Dominici M Tucci M Brunetti O Dammacco F Silvestris F 《British journal of haematology》2012,157(5):586-598
Recently, genetically modified mesenchymal stem cells (MSCs) have been exploited to deliver anti-cancer bio-drugs directly within the tumour mass. Here, we explored whether adipose-derived MSCs (AD-MSCs), engineered to express the pro-apoptotic ligand TRAIL (also known as TNFSF10), kill multiple myeloma (MM) cells and migrate towards MM cells in vitro. Different MM cell lines were assessed for their sensitivity to recombinant human (rh) TRAIL alone and in combination with the proteasome inhibitor bortezomib, which was shown to enhance the effect of rhTRAIL. TRAIL(+) -AD-MSCs were co-cultured with bortezomib-pretreated MM cells and their killing activity was evaluated in presence or absence of caspase inhibition. AD-MSC migration towards media conditioned by both myeloma cells and myeloma bone fragments was also investigated. Despite moderate MM cell sensitivity to rhTRAIL, TRAIL(+) -AD-MSCs in combination with bortezomib significantly induced myeloma cell death. This effect was associated with caspase-8 activation and abrogated by capsase inhibition. On the other hand, co-culture experiments were performed to evaluate whether unmodified AD-MSCs affect myeloma cell growth in vitro. AD-MSCs appeared ineffective on myeloma cell growth and showed migratory capacity towards MM cells in vitro. These data emphasize the anti-myeloma activity of TRAIL-engineered AD-MSCs and provide support for a future model of a cell-based approach against MM. 相似文献
992.
AA Toor KK Payne HM Chung RT Sabo AF Hazlett M Kmieciak K Sanford DC Williams WB Clark CH Roberts JM McCarty MH Manjili 《British journal of haematology》2012,158(6):700-711
Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza‐Rev and cryopreserved. Subsequent stem cell mobilization was followed by high‐dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up‐regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)‐specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT. 相似文献
993.
994.
995.
Kim J Denu RA Dollar BA Escalante LE Kuether JP Callander NS Asimakopoulos F Hematti P 《British journal of haematology》2012,158(3):336-346
Multiple myeloma (MM) is characterized by almost exclusive tropism of malignant cells for the bone marrow (BM) milieu. The survival and proliferation of malignant plasma cells have been shown to rely on interactions with nonmalignant stromal cells, in particular mesenchymal stromal cells (MSCs), in the BM microenvironment. However, the BM microenvironment is composed of a diverse array of cell types. This study examined the role of macrophages, an abundant component of BM stroma, as a potential niche component that supports malignant plasma cells. We investigated the proliferation of MM tumour cell lines when cultured alone or together with MSCs, macrophages, or a combination of MSCs and macrophages, using the carboxyfluorescein succinimidyl ester assay. Consistently, we observed increased proliferation of MM cell lines in the presence of either MSCs or macrophages compared to cell line-only control. Furthermore, the combined co-culture of MSCs plus macrophages induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, MSCs and macrophages decreased the rate of apoptosis of myeloma cells. Our in vitro studies provide evidence that highlights the role of macrophages as a key component of the BM microenvironment facilitating the growth of malignant plasma cells in MM. 相似文献
996.
Hosen N Ichihara H Mugitani A Aoyama Y Fukuda Y Kishida S Matsuoka Y Nakajima H Kawakami M Yamagami T Fuji S Tamaki H Nakao T Nishida S Tsuboi A Iida S Hino M Oka Y Oji Y Sugiyama H 《British journal of haematology》2012,156(2):213-224
Monoclonal antibody (mAb) drugs are desirable for the improvement of multiple myeloma (MM) treatment. In this study, we found for the first time that CD48 was highly expressed on MM plasma cells. In 22 out of 24 MM patients, CD48 was expressed on more than 90% of MM plasma cells at significantly higher levels than it was on normal lymphocytes and monocytes. CD48 was only weakly expressed on some CD34(+) haematopoietic stem/progenitor cells, and not expressed on erythrocytes or platelets. We next examined whether CD48 could serve as a target antigen for mAb therapy against MM. A newly generated in-house anti-CD48 mAb induced mild antibody-dependent cell-mediated cytotoxicity and marked complement-dependent cytotoxicity against not only MM cell lines but also primary MM plasma cells in vitro. Administration of the anti-CD48 mAb significantly inhibited tumour growth in severe combined immunodeficient mice inoculated subcutaneously with MM cells. Furthermore, anti-CD48 mAb treatment inhibited growth of MM cells transplanted directly into murine bone marrow. Finally and importantly, we demonstrated that the anti-CD48 mAb did not damage normal CD34(+) haematopoietic stem/progenitor cells. These results suggest that the anti-CD48 mAb has the potential to become an effective therapeutic mAb against MM. 相似文献
997.
目的 探讨熊去氧胆酸(UDCA)对α-萘异硫氰酸酯(ANIT)诱导大鼠胆汁淤积性肝损伤的保护作用及作用机制.方法 取SD大鼠48只,其中42只以ANIT 100 mg/kg灌胃造成急性肝损伤,在肝损伤后24 h处死6只,其余均分为对照组和UDCA组各18只.对照组予0.9%NaCl溶液灌胃,UDCA组予20 mg/kg UDCA灌胃,分别在造模后48、72、96 h各处死6只,另6只不予处理为空白对照组.所有大鼠处死留取血清和肝组织,检测血清ALT、AST、Tbil、总胆汁酸(TBA),ELISA法检测血清IL-10、IL-6、TNF-α,实时荧光定量PCR检测肝组织多药耐药相关蛋白2(Mrp2) mRNA,HE染色观察肝组织炎性反应活动度.结果 肝损伤造模后48 h,UDCA组和对照组血清Tbil[(143.80±12.08) μmol/L比(178.50±15.19)μmol/L]、TBA[( 13.15±3.81) μmol/L比(21.68±7.93)μmol/L]、IL-10[(44.13±3.68)ng/L比(37.15±6.25)ng/L]、IL-6[(50.80±2.09) ng/L比(57.32±4.63)ng/L]、TNF-α[(17.53±0.84)ng/L比(19.10±1.64) ng/L]比较,差异均有统计学意义(P<0.01或P<0.05);肝损伤造模后72 h,UDCA组和对照组血清ALT[(721.67±97.54)U/L比(929.50±148.29)U/L]、IL-10[(54.68±6.79)ng/L比(43.85±4.08)ng/L]比较,差异均有统计学意义(P<0.01或P<0.05);肝损伤造模后96 h,UDCA组和对照组血清ALT[(156.83±14.99)U/L比(250.67±42.29)U/L]、AST[(143.67±27.45) U/L比(206.00±63.94)U/L]、Tbil[(23.53±5.08)μmol/L比(34.02±9.98)μmol/L]比较,差异有统计学意义(P<0.01或P<0.05).肝损伤造模后UDCA组和对照组肝组织Mrp2 mRNA表达在48 h(0.77±0.21、0.46±0.25)、72 h(2.27±0.84、1.10±0.38)、96 h(3.64±0.54、2.75±0.69)各时间点差异均有统计学意义(P<0.01或P<0.05).结论 UDCA对ANIT诱导的胆汁淤积性肝损伤保护作用机制可能和调控血清细胞因子及肝脏Mrp2表达有关. 相似文献
998.
E. Chalayer K. Augeul-Meunier B. Tardy-Poncet P. Cathebras D. Guyotat B. Tardy 《La Revue de médecine interne / fondée ... par la Société nationale francaise de médecine interne》2012
The incidence of venous thromboembolism in multiple myeloma depends on the disease characteristics that include recent diagnosis, persistent or recurrent multiple myeloma, patient characteristics, and the type of treatment received such as thalidomide or lenalidomide especially in combination with high-dose dexamethasone, or combined chemotherapy. Currently, recommendations could be challenged by the results of the first randomized study evaluating aspirin, low molecular weight heparins and vitamin K antagonists in the antithrombotic prophylaxis. The recent data from the literature show that it is not possible to propose a therapeutic management for venous thromboembolism prophylaxis in multiple myeloma and that the use of antithrombotic prophylaxis may not be mandatory. 相似文献
999.
Pereira MJ Palming J Rizell M Aureliano M Carvalho E Svensson MK Eriksson JW 《Molecular and cellular endocrinology》2012,355(1):96-105
Rapamycin is an immunosuppressive agent used after organ transplantation, but its molecular effects on glucose metabolism needs further evaluation. We explored rapamycin effects on glucose uptake and insulin signalling proteins in adipocytes obtained via subcutaneous (n=62) and omental (n=10) fat biopsies in human donors. At therapeutic concentration (0.01 μM) rapamycin reduced basal and insulin-stimulated glucose uptake by 20-30%, after short-term (15 min) or long-term (20 h) culture of subcutaneous (n=23 and n=10) and omental adipocytes (n=6 and n=7). Rapamycin reduced PKB Ser473 and AS160 Thr642 phosphorylation, and IRS2 protein levels in subcutaneous adipocytes. Additionally, it reduced mTOR-raptor, mTOR-rictor and mTOR-Sin1 interactions, suggesting decreased mTORC1 and mTORC2 formation. Rapamycin also reduced IR Tyr1146 and IRS1 Ser307/Ser616/Ser636 phosphorylation, whereas no effects were observed on the insulin stimulated IRS1-Tyr and TSC2 Thr1462 phosphorylation. This is the first study to show that rapamycin reduces glucose uptake in human adipocytes through impaired insulin signalling and this may contribute to the development of insulin resistance associated with rapamycin therapy. 相似文献
1000.
Rosiñol L García-Sanz R Lahuerta JJ Hernández-García M Granell M de la Rubia J Oriol A Hernández-Ruiz B Rayón C Navarro I García-Ruiz JC Besalduch J Gardella S López Jiménez J Díaz-Mediavilla J Alegre A San Miguel J Bladé J;PETHEMA/Spanish Myeloma Group 《Haematologica》2012,97(4):616-621