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Introduction of bortezomib, the first generation of proteasome inhibitor, has significantly improved the median overall survival of patients with multiple myeloma (MM). However, the dose-limiting adverse events and acquired drug resistance limit its long-term usage. Here, we report in vitro and in vivo anti-MM activity of the irreversible proteasome inhibitor BSc2118. BSc2118 inhibited the chymotrypsin-like (CT-L) proteasome activity, accompanied by accumulation of ubiquitinated proteins. BSc2118 suppressed tumor cell growth through induction of G2/M phase arrest and induced apoptosis via activation of the apoptotic signaling cascade, in association with up-regulation of p53 and p21. Importantly, BSc2118 was active in vitro against MM cells' acquired bortezomib resistance. Of note, BSc2118 also displayed a novel anti-angiogenesis activity both in vitro and in vivo . Lastly, BSc2118 exhibited a broader safety dose range and higher anti-tumor efficacy in vivo in a human MM xenograft mouse model, compared to bortezomib. Together, these findings indicate the in vitro and in vivo anti-MM activities of BSc2118 through induction of cell cycle arrest and apoptosis, as well as inhibition of tumor angiogenesis. They also suggest that BSc2118 might, at least in vitro , partially overcome acquired bortezomib resistance, likely associated with inhibition of autophagy. [ABSTRACT FROM AUTHOR]

The common features shared by primary plasma cell leukemia (pPCL) and multiple myeloma (MM) with circulating plasma cells (CPCs) are peripheral blood invasion and expansion of plasma cells independent of the protective bone marrow (BM) microenvironment niche. However, few studies have addressed the relationship between pPCL and MM with CPCs. Here, we quantitated the number CPCs by conventional morphology in 767 patients with newly diagnosed MM; their clinic features were compared with those of 33 pPCL cases. When the presence of CPCs was defined as more than 2 % plasma cells per 100 nucleated cells on Wright-Giemsa stained peripheral blood smears, the incidence of MM with CPCs was 14.1 % in newly diagnosed MM. Patients with CPCs shared many clinical features with pPCL, especially clinical parameters related to tumor burden. However, no commonalities were found in immunophenotyping and cytogenetics. The prognosis of pPCL was poor, with a median progression free survival (PFS) of 12 months and an overall survival (OS) of 15 months. MM patients with CPCs had a clearly inferior PFS and OS as compared with the control cohort. Most interestingly, although the CPCs were not high enough to meet the diagnostic criteria for pPCL, the survival of MM patients with CPCs was comparable with that of pPCL, with a median PFS of 17 months and an OS of 25 months. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between total homocysteine (tHcy) and carotid intima-media thickness (CIMT) in brain infarction patients. Methods Sixty patients with fasting plasma tHcy levels ≤10 µmol/L (non-Hhcy group), 60 patients with fasting plasma tHcy levels >10 µmol/L and ≤15 µmol/L (H1 group), and 60 patients with fasting plasma tHcy levels >15 µmol/L (H2 group) were chosen in hospitalized patients with acute cerebral infarction. Values of CIMT were detected in three groups of patients. The clinical biochemical indicators including triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting blood sugar (FBS), folic acid (FA), Vitamin B12 (VitB12) and glycated hemoglobin (HbA1c) were also detected. Results There was significant difference in CIMT between three groups (P<0.01). The value of CIMT increased in H2 group [0.98(0.90, 1.05)mm] compared with that of non-Hhcy group [0.85(0.80, 0.95)mm]. The value of CIMT increased in H2 group compared with H1 group [0.98(0.90, 1.05)mm vs 0.85(0.85, 0.95)mm], P < 0.05). There were significant differences in tHcy, FA and VitB12 between three groups. Based on the log-transformed values of CIMT as the dependent variable, multiple stepwise linear regression showed significant associations of the following variables with increased CIMT: increasing age, the history of smoking, the history of diabetes, higher LDL-C and tHcy levels. Conclusion Brain infarction in patients with higher tHcy level often have lower levels of FA and VitB12, and increased CIMT. When the level of tHcy >15 µmol/L, there is more significantly higher level of CIMT. The increased CIMT level was associated with some cerebrovascular risk factors in patients with brain infarction. [ABSTRACT FROM AUTHOR]