靶向缺氧肿瘤微环境在多发性骨髓瘤治疗中的机制研究进展

多发性骨髓瘤(multiple myeloma,MM)作为一种高度异质性的难治性浆细胞肿瘤,与多数实体瘤类似,暴露于缺氧的肿瘤微环境中。缺氧条件下促进缺氧诱导因子(hypoxia inducible factor-1,HIF-1)活化及其作为转录因子参与的下游信号通路的激活,作用于肿瘤血管形成,骨髓瘤细胞的播散与转移,影响抗肿瘤免疫,促进肿瘤免疫逃逸,以及改变细胞能量代谢,参与诱导治疗耐药。基于上述机制,本文分别从靶向HIFs因子或信号通路的直接抑制,改善代谢、增加氧合,靶向免疫检查点恢复有效肿瘤免疫,抗血管形成等方面对靶向缺氧微环境的治疗在MM中的研究现状进行综述。

Oncolytic adenovirus targeting LASP-1 inhibited renal cell cancerprogression

Recent studies suggested that LIM and SH3 protein 1(LASP-1)is a promising therapeutic target for renal cell cancer(RCC).This study aimed to explore the role of LASP-1 in RCC.For this purpose,LASP-1 expression in RCC tissues was analyzed by immunohistochemistry and Western blot analysis.Cell proliferation,migration,invasion,and gene expression were detected by CCK-8 assay,Transwell assay,and Western blot analysis.The results showed that LASP-1 was highly expressed in RCC,and its expression level,t was positively correlated with lymph node metastasis and tumor,nodes,and metastases(TNM)stage.The knockdown of LASP-1 expression significantly inhibited the proliferation of RCC cells,increased the apoptosis rate,and inhibited RCC cell invasion and migration by inhibiting epithelial–mesenchymal transition.We conclude that LASP-1 promotes RCC progression and metastasis and is a promising therapeutic target for RCC.

Wortmannin induced apoptosis of leukemia cells by reducing PI3K/Akt

Objective： We studied the effects of Wortmannin （WM） on the proliferation and apoptosis of leukemia cells, and explore the possible mechanisms. Methods： The human myeloid leukemia cell line K562 was treated with different concentrations of WM, and then detected the activity of the cell proliferation by MTT assay, comet tail formation of cell DNA damage phenomenon by single cell gel electrophoresis, cell apoptosis byAnnexin V-FITC/PI double staining and the expression levels of total Akt, phoshorylated Akt, NF-KB and protein in K562 cell by Western blotting, RT-PCR test before and after WM. Results： WM inhibited cell proliferation of K562 in a concentration-dependent manner, with IC50 value for 24 h being 25 nmol/L. WM induced apoptosis of K562 cells in a concentration-dependent manner, and could induce the breakage of DNA strand of K562 cell. The rate of DNA tail and the tail length of experimental groups were significantly higher than that of control group. WM may inhibit the expression of phosphorylated Akt and NF-KB protein in a dose-dependent manner in both the protein and gene levels, but no significant effect on total Akt protein. Conclusion： WM inhibited cell proliferation and induced apoptosis in K562 and concentration-dependent manner. The possible mechanism may be involved in the regulation of survival signaling pathway, such as PI3K/Akt/NK-KB.

Study of Celastrol on Akt Signaling Pathway and Its Roles in the Apoptosis of K562 Cells

The purpose Celastrol, the main active compound of the Celastrus genus plants, belonging to Celastraceae, has recently marked antitumour potency on solid tumours of various derivations, Methods: We demonstrate here that Celastrol also present powerful antileukaemic potency through both growth arrest and apoptosis induction in K562 cells, which was accompanied by typical apoptotic morphological and sharp decreased expression of phosphorylation level of Caspase family members and Akt signaling pathway related proteins were determined by western blot before and after celastrol treatment, and further the effect of AKT signaling pathway on celastrol-induced-apoptosis was analyzed. However, in vitro treatment with Celastrol resulted in significantly reduced expression of phophorylation of Akt, Survivin and Bcl-2 significantly in K562 cells. Results: 25 nmol/L WORT (PI3K-Akt inhibitor) can significantly augmented cell apoptosis induced by Celastrol in K562 cells in dose-dependent manner, Moreover, most Caspase3,8,6 were activated in K562 cells during Celastrol treatment, 50 μmol/Lz-VAD-fmk (Caspase inhibitor) can to enhance the apoptosis induced by Celastrol. Discussion: These results suggest that the fact that Akt signaling pathway might act as new targets of Celastrol, correlates well with the sensitivity to Celastrol, as well as the rate of apoptosis induced by Celastrol, Mechanisms that regulate Akt signaling pathway may be provide novel opportunities for drug development.

Chinese expert consensus on the management of chimeric antigen receptor T cell therapy-associated coagulopathy

Chimeric antigen receptor T-cell(CAR-T)therapy has greatly improved the disease remission rate and long-term survival rate of patients with relapsed/refractory hematological malignancies.[1-3]Currently,several commercial CAR-T products are available in the market and numerous CAR-T clinical trials have been conducted.Attention should be paid to the safety of CAR-T therapy.The main adverse effects of CAR-T therapy are cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS).[4]

A SIMPLE SMOOTH EXACT PENALTY FUNCTION FOR SMOOTH OPTIMIZATION PROBLEM

For smooth optimization problem with equMity constraints, new continuously differentiable penalty function is derived. It is proved exact in the sense that local optimizers of a nonlinear program are precisely the optimizers of the associated penalty function under some nondegeneracy assumption. It is simple in the sense that the penalty function only includes the objective function and constrained functions, and it doesn＇t include their gradients. This is achieved by augmenting the dimension of the program by a variable that controls the weight of the penalty terms.

A ONE-PARAMETER FILLED FUNCTION FOR NONSMOOTH GLOBAL OPTIMIZATION AND ITS APPLICATION

This paper presents a modified definition of the filled function for finding a global minimizer of a nonsmooth function on a closed bounded set, and then give a one-parameter filled function. Theoretical and numerical properties of the proposed filled function are investigated and a corresponding solution algorithm is proposed. The proposed filled function＇s parameter is easier to be appropriately chosen than previous functions in literatures. Numerical results obtained indicate the efficiency of the proposed filled function method. An improved fingerprint recognition method using global filled function is also reported.