Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion ofbone marrow plasmacytes.It accounts for 10 ％ of all hematological malignancies.The proteasome,an intracellular enzyme complex that degrades ubiquitin-tagged proteins to regulate protein levels within the cell,plays an important role in maintaining cellular homeostasis.Proteasome inhibitors proved to be significantly effective in the clinical treatment of MM.In recent years,the application of the proteasome inhibitor has led to increased survival rates in MM patients.Bortezomib is the first proteasome inhibitor that has been approved by the US Food and Drug Administration due to its ability to reversibly inhibit the 26 s proteasome functions.Despite the fact that Bortezomib improves medical treatment,many patients experience difficulty responding to this drug and some patients who do respond eventually relapse.These results have led researchers to investigate new proteasome inhibitors with mechanisms different from those of Bortezomib.Some drugs that bind to the active site of the proteasome and irreversibly inhibit the complex have recently been developed and are currently being tested in advanced clinical trials.Here,we will elaborate on the proteasome inhibitors targeting MM and focus on newly discovered inhibitors that may overcome the resistance to Bortezomib.

Antigens, CD34 ; metabolism ; Diagnosis, Differential ; Fibrosarcoma ; metabolism ; pathology ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Mucocele ; metabolism ; pathology ; Myxoma ; metabolism ; pathology ; surgery ; Skin Neoplasms ; metabolism ; pathology ; surgery ; Toes ; Vimentin ; metabolism

Objective To observe the level of reduced glutathione(GSH) and oxidized glutathione(GSSG)in a mouse bone cell line MC3T3-E1 cells exposed to fluoride.Methods MTT method was used to detect cell viability of M C3T3-E1 cells exposed to varying concentrations and periods of fluoride [F-concentration:0(control),0.5,1.0,2.0,4.0,8.0,12.0,20.0 mg/L; F-periods:1,2,4 and 10 days].The Xevo TQ MS was employed to test the levels of GSH,GSSG and glutamine (Gln).Results The MC3T3-E1 cell viability was significantly higher in the 2 mg/L group(0.57 ± 0.05) 1 day after the exposure compared to the respective control(0.49 ± 0.03,P ＜0.01); conversely,cell viability was markedly lower in the 8 mg/L(0.49 ± 0.07) and 12 mg/L(0.47 ± 0.09)groups 4 days after the exposure in comparison to the control(0.63 ± 0.06,P ＜ 0.05 or P ＜ 0.01).The cell viability in the 8 mg/L group(1.52 ± 0.29) 10 days after the exposure was significantly higher than that in the control group (0.86 ± 0.23,P ＜ 0.01),however,the value in the 20.0 mg/L group (0.54 ± 0.07) was significantly lower(P ＜0.01).The level of cell GSH decreased significantly in the 20 mg/L groups 2 days[(13.92 ± 4.63)μmol/L]and 10 days [(0.53 ± 0.30)μmol/L]after exposure compared to the respective comtrols [(26.42 ± 3.67),(24.85 ± 5.68)μmol/L,all P ＜ 0.01].The level of cell GSSG markedly increased in the 2 mg/L group 2 days [(1.12 ± 0.62)μ mol/L]and the 8 mg/L group 4 days [(2.13 ± 0.62)μ mol/L]after exposure compared to the controls[(0.55 ± 0.22),(1.46 ± 0.46)μmol/L,all P ＜ 0.05].The similar change was observed in the 8 mg/L group[(2.97 ± 1.30)μmol/L] 10 days after exposure compared to the control [(1.35 ± 0.50)μmol/L,P ＜ 0.05].The level of Glndecreased significantly in the 2 mg/L group[ (62.80 ± 17.4l)μ mol/L] 4 days and in the 8 and 20 mg/L groups 10 days[ (122.26 ± 19.51), (19.38 ± 8.11)μmol/L] after exposure compared to the controls [ (83.28 ±14.32), ( 147.15± 16.95) μmol/L , all P ＜ 0.05 or P ＜ 0.01 ]. Conclusions Fluoride exposure can significantly promote the changes of GSH, GSSG and Gln levels in the osteoblast, thus affecting the intracellular redox equilibrium.

Objective To investigate the value of functional MRI in the diagnosis and differential diagnosis of breast diseases.Methods Sixty-five patients with 68 lesions were enrolled in this study. Conventional T_1 WI and T_2 WI scan,dynamic contrast enhanced MRI,diffusion weighted imaging and ~1H single voxel MR spectroscopy were performed consequently.All lesions were verified by pathology,including 4 cases of breast adenosis,22 fibroadenomas,2 chronic inflammations,3 cysts,33 infitrating ductal carcinomas,1 intraductal carcinoma and 3 cystosarcoma phyllodes tumors.Morphological features,maximum enhancement ratio,time-intensity curve,apparent diffusion coefficient and Choline peak were analyzed. Results The detection rates of T_1 WI and T_2 WI were 14.7%(n=10)and 51.5%(n=35).The sensitivity,specificity,accuracy of dynamic contrast.enhanced MRI for the malignant tumor were 94.6%, 71.4% and 76.5% respectively.Retrospective study showed that diffusion weighted imaging,with the b value from 800 s/mm~2 to 1000 s/mm~2,could be used to differentiate various types of breast lesions.~1H signal voxel spectroscopy had a sensitivity of 51.4%,specificity of 82.6%,and accuracy of 67.6% for the malignent.The sensitivity,specificity and accuracy could reach 97.3%,90.0% and 92.6% respectively by combining conventional scan,dynamic contrast enhanced MRI and MR spectroscopy.Conclusion Functional MRI,with high sensitivity,specificity and accuracy,can be used widely in the diagnosis of malignant breast lesions.

Alfimeprase(ALF)is a recombinantly modified variant of non-hemorrhagic zinc metalloproteinase fibrolase.The target gene alf was obtained from the clone vector p43-alf and cloned into the Pichia pastoris expression vector pPICZ? A.Through high efficiency transformation and Zeocin selection,the recombinant strains of pPICZ?A-alf /GS115 were isolated.In order to achieve a high level expression of recombinant Alfimeprase(rALF),optimization of pH value,methanol daily addition concentration,cell density and methanol induction time points were carried out,and the production of rALF reached up to 425 mg/L.By His?Bind chromatography,the purity of secreted rALF was as high as 95 %.SDS-PAGE and Western blot analysis show that rALF has a molecular weight of about 24 kDa and is bound specifically to anti-His?tag monoclonal antibody.Activity identification results of the modified fibrin plate method demonstrate that the secreted rALF has high fibrinolytic activity.Thus sets up an optimized expression system for ALF,which will play an important role in its further studies and industrial production.

Adult ; Humans ; Male ; Middle Aged ; Neoplasms, Neuroepithelial ; radiotherapy ; surgery

Reduced radiosensitivity of lung cancer cells represents a pivotal obstacle in clinical oncology. The hypoxia-inducible factor (HIF)-1α plays a crucial role in radiosensitivity, but the detailed mechanisms remain elusive. A relationship has been suggested to exist between hypoxia and autophagy recently. In the current study, we studied the effect of hypoxia-induced autophagy on radioresistance in lung cancer cell lines. A549 and H1299 cells were cultured under normoxia or hypoxia, followed by irradiation at dosage ranging from 0 to 8 Gy. Clonogenic assay was performed to calculate surviving fraction. EGFP-LC3 plasmid was stably transfected into cells to monitor autophagic processes. Western blotting was used to evaluate the protein expression levels of HIF-1α, c-Jun, phosphorylated c-Jun, Beclin 1, LC3 and p62. The mRNA levels of Beclin 1 were detected by qRT-PCR. We found that under hypoxia, both A549 and H1299 cells were radio-resistant compared with normoxia. Hypoxia-induced elevated HIF-1α protein expression preferentially triggered autophagy, accompanied by LC3 induction, EGFP-LC3 puncta and p62 degradation. In the meantime, HIF-1α increased downstream c-Jun phosphorylation, which in turn upregulated Beclin 1 mRNA and protein expression. The upregulation of Beclin 1 expression, instead of HIF-1α, could be blocked by SP600125 (a specific inhibitor of c-Jun NH2-terminal kinase), followed by suppression of autophagy. Under hypoxia, combined treatment of irradiation and chloroquine (a potent autophagy inhibitor) significantly decreased the survival potential of lung cancer cells in vitro and in vivo. In conclusion, hypoxia-induced autophagy through evaluating Beclin1 expression may be considered as a target to reverse the radioresistance in cancer cells.

Objective To study the value of fast dynamic contrast enhanced MRI in the diagnosis of orbital occupying lesions. Design Retrospective ease series.Participants 21 patients with orbital occupying lesions.Methods All the 21 patients were performed on fast dynamic contrast enhanced MRI and were verified by pathology.The raw datum were processed by the software of GE Functool. Parameters such as time-intensity curve(TIC),time to peak(Tpeak),1 minute enhancement ratio(ERlmin)and maximum enhancement ratio(ERmax)were analyzed to study the characteristics of orbital diseases on fast dynamic contrast-enhanced MRI.Main Outcome Measures TIC,ERlmin,and ERmax.Results The characteristics of TIC between benign diseases and malignant tumors were different. Of the 16 cases of benign lesions,12 demonstrated as continuous increasing type,and of 5 cases of malignant lesions,3 cases of lym- phoma were all platform type.The ER1min of the malignant tumors(150.47?42.18)was higher than that of the benign lesions (101.37?43.02)(P=0.021).Cavernous hemangiomas had special progressing enhancing model.Conclusions Fast dynamic contrast enhanced MRI is valuable to distinguish malignant tumors from benign occupying lesions.(Ophthalmol CHN,2007,16:305-308)

AIM: To evaluate the safety and efficacy of intravitreal bevacizumab ( avastin ) injection in patients with exudative age related macular degeneration ( AMD) .
METHODS: The records of patients treated with intravitreal injection of 1. 75mg bevacizumab for AMD were retrospectively reviewed. All patients were evaluated by complete ophthalmic examination, optical coherence tomography and fundus fluorescein and/or indocyanine green angiography. Observation was made on the best corrected visual acuity ( BCVA) , intraocular pressure, and the changes of lens, vitreous, central retinal thickness (CFT) and total macular volume (TMV), at 1d, 3d, 7d, 1mo and 6mo after the treatment and then compared with those of pre - operation. Repeated treatment with intravitreous bevacizumab occurred if there were signs of persistent or recurrent exudation. And all cases were followed up at least 6mo. An intravitreal injection of bevacizumab (1. 75mg) was given once every 6wk.
RESULTS:All 50 eyes of 48 patients with the average of 58±20. 46 years old were included. The mean baseline of BCVA and CFT were 0. 82±0. 53, and 364. 97±151. 83μm respectively. Although there was no significant decrease in mean CFT and TMV one week after the injection, the mean BCVA had significant improvement. At the last visit of 9. 7mo follow - up, BCVA, CRT and TMV showed significant improvements over baseline values. BCVA was improved by at least two lines in 32 eyes (64%),remained stabilization in 18 eyes (36%) at the last visit. A total of 98 injections were performed and the average number of injections was 1. 98 for each eye in the group. About 50%of re - injections gained at least two lines of vision improvement one week postoperatively. There were no serious adverse events during the treatment.
CONCLUSION: Intravitreal bevacizumab ( avastin ) injection for managing CNV due to age-related macular degeneration is safe and few side effects. Intravitreal avastin associated with improvement in visual acuity ( VA ) , which can reduce macular edema and choroidal neovascularization leakage. But a prolonged treatment effect needs further observation.

To evaluate the safety and efficacy of intravitreal bevacizumab injection in patients with macular edema (ME) induced by retinal vein occlusion (RVO).
● METHODS: The records of patients treated with intravitreal injection of 1. 75mg bevacizumab for ME induced by RVO were retrospectively reviewed. All patients were evaluated by complete ophthalmic examination, optical coherence tomography ( OCT) and fundus fluorescein angiography ( FFA ), etc. Best corrected visual acuity (BCVA), intraocular pressure, the change of lens and vitreous, central foveal thickness (CFT) were observed at 1, 2, 3, 6mo after treatment and compared with before treatment. Repeated treatment with intravitreous bevacizumab occurred if there were signs of persistent or recurrent exudation. All the cases were followed up at least 6mo. An intravitreal injection of bevacizumab (1. 75mg) was given at 6wk intervals.
●RESULTS: Fifty patients (56 eyes) with the average of (57±18. 56) years old were included. The mean baseline of BCVA, CFT were (logMAR0. 82±0. 63), (626. 5±178. 0)μm respectively. Although there was no significant decrease in mean CFT at 1wk after injection, the mean BCVA had significant improvement. Followed up at mean 10. 26 ± 5. 87mo, BCVA, CFT showed significant improvements over baseline values. The statistics of CFT at 1, 2, 3mo after injection were significant differences compared with before injection in each of the three groups. CFT at 1, 3, 12mo after injection were (365. 11±23. 212) μ m, (333. 42± 35. 526) μ m, (267. 6 ± 116. 8) μ m, which had a significant difference ( P < 0. 001), namely macular retinal thickness was thinner obviously that before treatment, ME was improved obviously. CFT was no significant difference at each time point after injection in the group of BRVO-ME and CRVO- ME (P> 0. 05). OCT image showed that after injection macular retinal thickness was becoming thinner. FFA showed that after injection macular fluorescein leakage decreased. BCVA was improved by at least two lines in 48 eyes (86%),remained stable in 8 eyes (14%) at the last visit. A total of 112 injections were performed and the average number of injections was 1. 96 in the group. About 50% of reinjections gained at least two lines of vision improvement at 1wk following the retreatment. There was no serious complications during the treatment.
●CONCLUSlON: lntravitreal injection of bevacizumab can improve visual acuity (VA) of RVO (CRVO and BRVO) in patients with ME, relieve ME, reduce the leakage of CNV, and repeated treatment is better. But a prolonged treatment effect needs further observation. There are no serious ocular and systemic complications occurred in our study.