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.

Despite many recent advances in the treatment of multiple myeloma (MM), the course of the disease is characterized by a repeating pattern of periods of remission and relapse as patients cycle through the available treatment options. Evidence is mounting that long-term maintenance therapy may help suppressing residual disease after definitive therapy, prolonging remission and delaying relapse. For patients undergoing autologous stem cell transplantation (ASCT), lenalidomide maintenance therapy has been shown to improve progression-free survival (PFS), however, it is still unclear whether this translates into extended overall survival (OS). For patients ineligible for ASCT, continuous therapy with lenalidomide and low-dose dexamethasone is shown to improve PFS and OS (interim analysis) compared with a standard, fixed-duration regimen of melphalan, prednisone, and thalidomide in a large phase Ⅲ trial. Other trials have also investigated thalidomide and bortezomib maintenance for ASCT patients, and both agents have been evaluated as continuous therapy for those who are ASCT ineligible. However, some important questions regarding the optimal regimen and duration of therapy must be answered by prospective clinical trials before maintenance therapy, and continuous therapy should be considered routine practice. This article reviewed the available data on the use of maintenance or continuous therapy strategies and highlights ongoing trials reported in the 57th American Society of Hematology (ASH) annual meeting that would help to further define the role of these strategies in the management of patients with newly diagnosed MM.

In this last decade,one of the major advances in the management of multiple myeloma has been the introduction of the novel agents thalidomide,bortezomib,and lenalidomide as part of treatment in young patients eligible for high-dose therapy (HDT) and autologous stem cell transplantation (ASCT).These drugs have markedly improved the rate of complete remission both before and after ASCT without substantially increasingly toxicity.The implementation of an ‘optimal strategy’ consisting of novel-agent-based induction,HDT,and the use of novel agents in consolidation and maintenance may result in 5-year survival rate of 80 ％ and cure might be considered in a subset of patients who present with good prognostic features at the time of diagnosis.Nevertheless,the high efficacy of the novel agents has led some groups to test these agents upfront without ASCT.At the end of 2014,preliminary randomized data favor early ASCT plus novel agents over novel agents alone.Therefore,the optimal approach to the treatment of multiple myeloma is still to propose the most effective treatment that should involve the use of frontline ASCT in young patients eligible for HDT.This article reviews the latest research presented at the 56th American Society of Hematology (ASH) annual meeting on the multiple myeloma and its clinical management.

Air ; Animals ; Diving ; Male ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; metabolism ; Spleen ; metabolism

Objective To investigate the effects of inhalation of different concentrations of isoflurane on the expression of cytochrome c ( Cyt c) in hippocampus in aged rats.Methods Sixty-three aged male SD rats (20 months) weighing 500-600 g were randomly divided into 3 groups(n=21each):control group inhaling 30%O2 for 2h (group C) and 2 isoflurane groups anesthetized with 0.75 % and 1.5 % isoflurane in 30 % O2 for 2 h respectively (group Ⅰ1 and Ⅰ2 ).Arterial blood samples were obtained from 5 rats at 30 min, 1 and 2 h of anesthesia for blood gas analysis. Eight animals were killed at 24 h after anesthesia in each group.Their hippocampi were immediately removed for determination of Gyt c expression by immuno-histochemistry and Western blot analysis.Cognitive function was assessed by Morris water maze test the day before experiment and once a day for 6 consecutive days starting from the 1st postoperative day.Results The Cyt c expression in hippocampus was significantly increased in Ⅰ1 and Ⅰ2 groups in a concentration-dependent manner as compared with group C.The escape latency was significantly prolonged and the frequency of crossing the original platform and the duration of staying at the original platform quadrant were decreased in group Ⅰ1 and Ⅰ2 compared with group C.Conclusion Inhalation of isoflurane anesthesia can decrease cognitive function through up-regulating the Gyt c expression in hippocampus in aged rats.

Objective To observe the change in memory of aged rats and the expression of alpha 4 acetylcholine receptor in hippocampus 5 h after inhalation of 1.2% isoflurane.Methods Fifty healthy adult and 50 aged SD rats were randomly divided into aged normal control group(A0),aged water labyrinth normal control group(WA0),1 day isoflurane aged water labyrinth group(WA1),3-day isoflurane aged water labyrinth group(WA3),7-day isoflurane aged water labyrinth group(WA7),adult normal control group(B0), adult water labyrinth normal control group(WB0),adult 1 day isoflurane water labyrinth group(WB1),3-day isoflurane water labyrinth group(WB3),and 7-day isoflurane water labyrinth group(WB7),10 rats in each group.Memory of rats in WA1,WA3,WA7 groups was detected 5 h after inhalation of 1.2% isoflurane while memory in rats of WB1,WB3 and WB7 groups was detected during the Morris water maze testing.The rats in A0,WA0,WA7,B0,WB0 and WB7 groups were killed on day 7 to detect the expression of ?4 acetylcholine receptor by Westernblotting for observation of changes in distribution of positive immune reaction cells in hippocampus.Results Water maze test showed that there was no significant difference in expression of alpha 4 acetylcholine receptor between WA0 and WB0 groups.However,the expression level of alpha 4 acetylcholine receptor was significantly lower in latent period of WA1 than in latent period of WA0,WB0 and WB7 groups(P

Objective To investigate the effects of isoflurane on receptor for advanced glycation endproducts (R(A)GE) expression in the hippocampus in rats. Methods Forty-five male 4-month-old and 45 male 24-month-old rats were used in this study. The animals were divided into 2 age groups ( n = 45 each): the aged group (group O) and the adult group (group A). Each group was further divided into 3 subgroups ( n = 15 each):Ⅰ control subgroup (group OC,AC) inhaled 30% O2 in air; 1 single isoflurane inhalation subgroup (group OS,AS) inhaled 1.5 % isoflurane for 2 h and Ⅲ repeated isoflurane inhalation subgroup (group OR, AR) inhaled 1.5 % isoflurane 2 h per day for 3 days. One day after isoflurane inhalation, learning and memory function was assessed using Morris water maze test in 8 animals in each subgroup. The rest of each subgroup were killed and their hippocampi were immediately isolataed for detection of RAGE mRNA and protein expression by RT-PCR and immuno-histochemistry. Results The cognitive function was impaired after signle or repeataed isoflurane anesthesia as compared with control animals in both aged and adult groups. The expression of RACE mRNA and protein in hippocampus was significantly increased after either single or repeated isoflurane anesthesia in aged group but only after repeated isoflurane anesthesia in adult gpoup. There was no significant difference in RAGE mRNA and protein expression in the hippocampus between control and single isoflurane inhalation animals in adult group. Conclusion Isoflurane can reduce learning and memory function in both aged and adult rats by increasing RAGE expression in hippocampus especially in aged rats.

Objective To explore the effect of isofluranee on receptor for advanced glycation end products (RAGE) expression of hippocampus and learning and memory function in rats. Methods 24-month Sprague-Dawley male rats (n=45) and 4-month Sprague-Dawley male rats (n=45) were randomly divided into six groups with 15 rats each group. Group C1 (aged control group),group C2(adult control group) breath 30% oxygen and air mixed gas; Group S1(single inhalation of isoflurane aged group),Group S2(single inhalation of isoflurane adult group)were anesthetized with 1.5% isoflurane,breath 30% oxygen and air mixed gas for 2h;Group R1(Repeated inhalation of isoflurane aged group), group R2(Repeated inhalation of isoflurane adult group) were anesthetized with 1.5% isoflurane,breath 30% oxygen and air mixed gas 2h a day for three days. Eight rats randomly selected from each group were killed and their hippocampus were immediately isolated for detection of RAGE expression by immunohistochemistry and RT-PCR after accomplished treatment 24h. The remained rats' learning and memory function were assessed using Morris water-maze test. Results The results of Morris water-maze test showed that the times of acerossing the original platform and the time consumption of staying the original platform quadrant was shorter in group S1 and group R1,but the escape latency was longer than group C1(escape latency C1 (9.42± 2.63)s,S1(13.20±3.85)s,R1(17.20±3.44)s, F=12.773, P<0.05). In the group R2,the escape latency was longer but the times of accrossing the original platform and the time consumption of staying the original plat-form quadrant was shorter than group C2 (times of accrossing the original platform C1(7.30±2.40), S1(3.90± 2.42),R1(3.44±2.40), F=7.448, P<0.01).To contrast with the group C2,there were no significant differ-enees in spatial probe test in the group S2(P>0.05). The levels of mRNA and protein of RAGE in hippocampus was significantly higher in group S1 and group R1 than group C1(RAGE mRNA expression C1(0.11±0.02),S1 (0.56±0.09), R1(0.73±0.14), F=179.447, P<0.01). To contrast with the group C2, there were no differ-ences found in the levels of mRNA and protein of RAGE in group S1(P>0.05), but it was higher in the group R2 (RAGE mRNA express C2(0.22±0.04), R2 (0.41±0.08), F=40. 209, P < 0. 01). Conclusion Isoflurane can reduce learning and memory function in both aged and adult rats, but aged rats are particularly significant im-pacted. This effect may be induced by the increase of RAGE expression in hippocampas.

Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twenty patients with simple ventricular septal defect (VSD) were chosen as controls, and 30 patients with PH were studied. Plasma levels of ET-1 and NO were measured by radioimmunoassay or colorimetric method. Before cardiopulmonary bypass was established, the specimens from right lung were fixed with formaldehyde solution, embedded with paraffin and stained by SP immunohistochemistry. Intercellular adhesion molecule-1 (ICAM-1) expression was measured through the determination of the light density with computer imaging technology. Results Compared with that of the patients with simple VSD, the light density of ICAM-1 and plasma level of ET-1 increased in patients with PH; but plasma level of NO decreased (P<0.05). Positive correlation was observed between ICAM-1 and ET-1/NO (P<0.05). Conclusion Endothelia cells activation and imbalance of ET-1/NO might play an important role in the development of PH.

Objective To investigate the change trend of liver function indicators in different types of hyperlipidemia patients. Methods From July 2014 to July 2015 ,a total of 2571 patients with hyperlipidemia and 1063 normal people(control group) were collected in this research.All patients with hyperlipidemia were divided into the hypercholesterolemia group (high TC group ,n=258) ,hypertriglyceridemia group (high TG group ,n=859) and mixed type hyperlipidemia group(n=282) ,low high-density lipo-protein cholesterol group(low HDL-c group ,n=1172).The liver function indicators of total protein (TP) ,albumin (ALB) ,alanine aminotransferase(ALT ) ,aspartate aminotransferase (AST ) ,AST/ALT and globulin (GLB ) were measured in each group. Results The TP and ALB levels in the high TC group ,mixed group and low HDL group were significantly decreased compared with the control group ,the difference was statistically significant (P<0.05).The ALT ,AST ,AST/ALT and GLB levels in the four hyperlipidemia groups had different degrees of increase as compared with the control group ,the difference was statistically signifi-cant(P<0.05).The TP and ALB levels in the mixed group and the low HDL group were significantly lower than those in the high TG group and high TC group ,the difference was statistically significant (P<0.05).The ALT level in the low HDL group was sig-nificantly higher than that in the other three groups ,the difference was statistically significant (P<0.05).The AST/ALT level in the mixed group was significantly higher than the other three groups (P<0.05).The GLB level in the high TC group was signifi-cantly higher than the other 3 groups with statistical difference (P<0.05).Conclusion Blood lipid increase may induce the liver function injury.The detection of liver function indicators in the patients with hyperlipidemia will contribute to the early detection and treatment of fatty liver.