Chronic intermittent hypoxia aggravates cardiomyocyte apoptosis in rat ovariectomized model

Background  The prevalence of obstructive sleep apnea (OSA) increases after menopause in women, but remains under diagnosed because of social or lifestyle factors. It is important to evaluate the hazards of OSA on cardiovascular disease in menopausal women. We tested the hypothesis that chronic intermittent hypoxia (CIH) may aggravate cardiomyocyte apoptosis in ovariectomized (OVX) Sprague Dawley (SD) rats; the changes of anti-oxidation ability in cardiac muscles may be one of the reasons for cardiomyocyte apoptosis.

Methods  Forty-eight 60-day old female SD rats were randomly divided into a CIH group, OVX group, OVX+CIH (OC) group, and handled control (HC) group, and the rats were exposed either to CIH (nadir O₂ 6%) or handled normoxic controls. The changes of body weight and whole heart weight were measured. Super oxide dismutase (SOD) and malonaldehyde (MDA) were used to evaluate the level of oxidative stress. TdT-mediated dUTP nick end labeling (TUNEL) was used to measure apoptosis in each rat. Western blotting was used to measure apoptosis associated proteins in cardiac muscle samples from each rat.

Results  When compared with the HC and CIH groups, the levels of oxidative stress in the OC and OVX groups were significantly higher. The levels of SOD in the HC, CIH, OC, and OVX groups were (47.99±4.89), (53.60±4.47), (20.99±2.72), and (30.64±3.79) mmol/mg protein; significantly increased in the CIH group (P <0.05) and significantly decreased in the OC (P <0.01) and OVX (P <0.05) groups. The levels of MDA in the HC, CIH, OVX, and OC groups were (1.63±0.20), (1.93±0.77), (3.30±0.39), and (1.95±0.20) mmol/mg protein; it significantly increased in the CIH (P <0.05), OC (P <0.01), and OVX (P <0.05) groups compared with the HC group. Bax protein expression was significantly increased and bcl-2 protein expression was significantly reduced after CIH compared with HC rats (P <0.05). The protein expression of bax and bcl-2 in the OC group was not significantly different from the CIH group, but the ratio of bax/bcl-2 was significantly increased in the OC group (P <0.05); this was associated with severe cardiomycyte apoptosis in the OC group. TUNEL confirmed this observation.

Conclusions  This study found that CIH may induce oxidative stress in OVX rats but not in CIH rats, and cause more severe cardiomyocyte apoptosis in OVX rats compared with CIH rats. This means that OVX rats exposed to CIH suffered more severe cardiac injury compared with CIH rats due to reduced antioxidation. These findings may partly explain the reason why OSA has a worse cardiovascular impact on menopausal women, and emphasize the importance of detection and early treatment of OSA in menopausal patients.

     

非肿瘤细胞凋亡引起肿瘤机体血清细胞色素C增高

Background  Neuroblastoma (NB) is one of the most common malignant solid tumors of childhood. It is still not clear whether the apoptosis of tumor cells or the non-tumor cells contributes to the increase of concentration of cytochrome c (Cyt c) in the serum of the cancer patients. The aim of this research was to identify the source of the Cyt c in the serum when the tumor grows up by subcutaneous inoculation of human NB cells into nude mice.

Methods  We subcutaneously inoculated human NB cells (KP-N-NS) into nude mice and collected the sera of tumor-bearing mice (n=14) and control mice (n=25) 4 weeks later in order to screen for and identify differentially expressed proteins in the serum. Differentially expressed proteins in the serum were screened by surface-enhanced laser desorption/ionization-time-of-flight (SELDI-TOF) mass spectrometry.

Results  The relative intensity of a protein having a mass-to-charge ratio (m/z) of 11 609 was 3338.37±3410.85 in the tumor group and 59.84±40.74 in the control group, indicating that the expression level of this protein in the tumor group was 55.8 times higher than that in the control group. Serum proteins were separated and purified by high-performance liquid chromatography (HPLC). Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to produce peptide mass fingerprints (PMFs). Spectrum analysis and a database search revealed that the highly expressed protein (m/z=11 605.4) from the serum of tumor-bearing mice was the mouse Cyt c.

Conclusions  Increased concentration of Cyt c in the serum of tumor-bearing nude mice might be partially attributed to the secretion of this protein by non-tumor cells.

     

Serum antibodies to 25 myelin oligodendrocyte glycoprotein epitopes in multiple sclerosis and neuromyelitis optica: clinical value for diagnosis and disease activity

Background  Whether antibody to myelin oligodendrocyte glycoprotein (MOG) can be a diagnostic marker for multiple sclerosis (MS) is still controversial. Recent studies suggested that serum specific anti-MOG epitope antibody might be an MS specific marker. However, these studies did not include neuromyelitis optica (NMO) which might be proven to also have anti-MOG antibody. Hence, the present study was undertaken to investigate the clinical value of serum antibodies to 25 MOG epitopes in conventional MS (CMS) and NMO.

Methods  Serum anti-MOG epitope IgG was detected in 61 CMS patients, 54 NMO patients, and 77 healthy controls, using enzyme-linked immunosorbent assay (ELISA).

Results  Anti-MOG_27-38 IgG levels in both CMS and NMO patients were significantly higher than that in healthy controls (optical density (OD): 0.64±0.38, 0.48±0.23 vs. 0.19±0.09; P=0.000). CMS and NMO patients in relapse stage had significantly higher anti-MOG_27-38 IgG level than patients in remission stage (OD: 0.55±0.14 vs. 0.24±0.09, P=0.027).

Conclusion  Although serum anti-MOG epitope IgG could not differentiate MS from NMO, it may be a useful marker for monitoring disease activity.

     

Effects of partial portal vein arterialization on liver regeneration after hepatectomy in minipigs with obstructive jaundice

Background  Hilar cholangiocarcinoma is a malignant tumor that is difficult to cure. BACKGROUNDThe aim of this study was to observe the effects of flow-controlled partial portal vein arterializations (PPVA) on liver regeneration after hepatectomy in minipigs with chronic obstructive jaundice.

Methods  Eight minipigs were made into chronic obstructive jaundice models. United semi-hepatectomy, which imitates extended radical surgery for treatment of hilar cholangiocarcinoma, was then performed. The eight minipigs were randomly divided into groups A and B (n=4 minipigs each). PPVA was performed in Group A but not in Group B. The effects of flow-controlled PPVA on live regeneration after hepatectomy were observed for 30 days after hepatectomy.

Results  The portal vein PO₂ at the immediate time point and on postoperative day 30 was higher in Group A ((47.33±2.43) and (48.50±4.44) mmHg) than in Group B ((35.38±4.06) and (35.55±2.55) mmHg respectively, all P <0.01). The mitotic index of liver cells on postoperative days 14 and 21 was higher in Group A (12.55%±2.85% and 15.25%±1.99% respectively) than in Group B (6.85%±2.10% and 11.88%±1.15% respectively, all P <0.05). The regeneration rate of residual liver on postoperative days 14 and 21 was higher in Group A (24.56%±6.15% and 70.63%±9.83% respectively) than in Group B (11.96%±5.43% and 44.92%±7.42% respectively, P <0.05 and P <0.01 respectively).

Conclusion  Flow-controlled PPVA can promote liver regeneration after hepatectomy and prevent liver failure in minipigs with chronic obstructive jaundice.

     

Cigarette smoking increases levels of retinol-binding protein-4 in healthy men with normal glucose tolerance

Background  Smoking is related with insulin resistance and type 2 diabetes mellitus. Retinol-binding protein-4 is a new adipocytokine associated with insulin resistance. We investigated the serum levels of a series of adipocytokines including retinol-binding protein-4 in smokers and non-smokers to explore the possible roles of adipocytokines on smoking induced insulin resistance.

Methods  A total of 136 healthy male subjects (92 smokers and 44 non-smokers) with normal glucose tolerance were enrolled in the study. Adipocytokines including retinol-binding protein-4, visfatin, leptin, resistin, adiponectin were measured for the comparison between the two groups. Serum lipid profile, glucose, true insulin and proinsulin levels were measured as well in both groups. Food intake spectrum was also investigated.

Results  Both groups had similar profile of food consumption; visfatin, leptin, resistin and adiponectin, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, as well as blood pressure and body mass index, were similar in both groups. Triglycerides, retinol-binding protein-4 and homeostatic model assessment index for insulin resistance were higher in smoker group ((2.58±2.53) vs. (1.60±0.94) mmol/L, (26.05±8.50) vs. (21.83±8.40) µg/ml, and 2.25±2.08 vs. 1.58±1.15, respectively).

Conclusion  Smoking may have effect on insulin sensitivity, which is correlated with retinol-binding protein-4.

     

Steady-state pharmacokinetics of zidovudine in Chinese HIV-infected patients

Background  The pharmacokinetics of zidovudine (AZT) are possibly influenced by weight, age, sex, liver and renal functions, severity of disease, and ethnicity. Currently, little information is available on the steady-state pharmacokinetics of AZT in Chinese HIV-infected patients. The current study aimed to characterize the steady-state pharmacokinetics of AZT in a Chinese set-up.

Methods  Eleven Chinese HIV-infected patients were involved in the steady-state pharmacokinetic study. In total, 300 mg of AZT, as a part of combination therapy, was given to patients, and serial blood samples were collected for 12 hours. The samples were measured by a high-performance liquid chromatography (HPLC) assay, and the results were analyzed by both the non-compartment model and the one-compartment model.

Results  The C_max of AZT in Chinese patients was higher than that in non-Asian patients. The half-life of AZT, analyzed by the non-compartment model (P=0.02), in male patients ((1.02±0.22) hours) was shorter than that of AZT in female patients ((1.55±0.29) hours). The AZT clearance, analyzed by the one-compartment model (P=0.045), in male patients ((262.60±28.13) L/h) was higher than that in female patients ((195.85±60.51) L/h).

Conclusion  The present study provides valuable information for the clinical practice of AZT-based highly active antiretroviral therapy in a Chinese set-up.

     

Endothelial progenitor cell down-regulation in a mouse model of Kawasaki disease

Background  Cardiovascular complications of Kawasaki disease (KD) are a common cause of heart disease in pediatric populations. Previous studies have suggested a role for endothelial progenitor cells (EPCs) in coronary artery lesions associated with KD. However, long-term observations of EPCs during the natural progression of this disorder are lacking. Using an experimental model of KD, we aimed to determine whether the coronary artery lesions are associated with down-regulation of EPCs.

Methods  To induce KD, C57BL/6 mice were administered an intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE; phosphate buffered saline used as control vehicle). Study groups included: group A (14 days following LCWE injection), group B (56 days following LCWE injection) and group C (controls). Numbers of circulating EPCs (positively staining for both CD34 and Flk-1 while staining negative for CD45) were evaluated using flow cytometry. Bone marrow mononuclear cells were cultured in vitro to expand EPCs for functional analysis. In vitro EPC proliferation, adhesion and migration were assessed.

Results  The model was shown to exhibit similar coronary artery lesions to KD patients with coronary aneurysms. Numbers of circulating EPCs decreased significantly in the KD models (groups A and B) compared to controls ((0.017±0.008)% vs. (0.028±0.007)%, P <0.05 and (0.016±0.007)% vs. (0.028±0.007)%, P <0.05). Proliferative, adhesive and migratory properties of EPCs were markedly impaired in groups A and B.

Conclusion  Coronary artery lesions in KD occur as a consequence of impaired vascular injury repair, resulting from excess consumption of EPCs together with a functional impairment of bone marrow EPCs and their precursors.

     

Ibutilide decreases defibrillation threshold by the reduction of activation pattern complexity during ventricular fibrillation in canine hearts

Background  Ibutilide has been commonly used for pharmacologic cardioversion of atrial fibrillation and flutter in clinical settings. The objective of this study was to investigate the effects of ibutilide on the defibrillation threshold (DFT), restitution properties, dispersion of refractoriness and activation patterns during ventricular fibrillation (VF).

Methods  Ibutilide was administrated intravenously in six open-chest beagles. Before and after the drug administration, 20-second episodes of VF were electrically induced and recorded with a 10×10 unipolar electrode plaque sutured on the lateral epicardium of the left ventricle. DFT and VF activation patterns, including type of epicardial activation maps, VF cycle length (VF-CL), conduction velocity, wavelength (WL) and reentry incidence, were measured. Restitution properties and dispersion of refractoriness were estimated from activation recovery intervals (ARI) during pacing.

Results  Compared to baseline, ibutilide markedly decreased the DFT by 31% ((491±14) V vs. (337±59) V, P <0.01). The drug significantly reduced the maximal slope of the restitution curve (1.34±0.08 vs. 0.76±0.06, P <0.01) and its epicardial dispersion (0.36±0.09 vs. 0.21±0.06, coefficient of variation, P=0.03). The dispersion of refractoriness was enhanced at the pacing cycle length of 300 ms to 160 ms by ibutilide. The drug significantly increased the VF-CL ((96±19) ms vs. (112±20) ms, P <0.01) and the WL ((41±9) mm vs. (52±14) mm, P=0.02) during VF, and reduced the reentry incidence by 25% (0.08±0.02 vs. 0.06±0.02, P <0.01). In the epicardial activation maps, ibutilide significantly reduced the percentage of more complex activation maps during VF.

Conclusions  Intravenous ibutilide significantly decreased the DFT. It might be due to reduction of activation pattern complexity during VF.

     

Ibutilide decreases defibrillation threshold by the reduction of activation pattern complexity during ventricular fibrillation in canine hearts

Background  Ibutilide has been commonly used for pharmacologic cardioversion of atrial fibrillation and flutter in clinical settings The objective of this study was to investigate the effects of ibutilide on the defibrillation threshold (DFT), restitution properties, dispersion of refractoriness and activation patterns during ventricular fibrillation (VF).

Methods  Ibutilide was administrated intravenously in six open-chest beagles. Before and after the drug administration, 20-second episodes of VF were electrically induced and recorded with a 10×10 unipolar electrode plaque sutured on the lateral epicardium of the left ventricle. DFT and VF activation patterns, including type of epicardial activation maps, VF cycle length (VF-CL), conduction velocity, wavelength (WL) and reentry incidence, were measured. Restitution properties and dispersion of refractoriness were estimated from activation recovery intervals (ARI) during pacing.

Results  Compared to baseline, ibutilide markedly decreased the DFT by 31% ((491±14) V vs. (337±59) V, P<0.01). The drug significantly reduced the maximal slope of the restitution curve (1.34±0.08 vs. 0.76±0.06, P<0.01) and its epicardial dispersion (0.36±0.09 vs. 0.21±0.06, coefficient of variation, P=0.03). The dispersion of refractoriness was enhanced at the pacing cycle length of 300 ms to 160 ms by ibutilide. The drug significantly increased the VF-CL ((96±19) ms vs. (112±20) ms, P<0.01) and the WL ((41±9) mm vs. (52±14) mm, P=0.02) during VF, and reduced the reentry incidence by 25% (0.08±0.02 vs. 0.06±0.02, P<0.01). In the epicardial activation maps, ibutilide significantly reduced the percentage of more complex activation maps during VF.

Conclusions  Intravenous ibutilide significantly decreased the DFT. It might be due to reduction of activation pattern complexity during VF.

     

Role of microRNA-181a in the apoptosis of tubular epithelial cell induced by cisplatin 

Background  Cisplatin (DDP) is one of most effective and most commonly used therapeutic agent in treating tumors, it can accumulate in the kidney and lead to acute renal failure. MicroRNA-181a can induce cell apoptosis by suppressing the expression of Bcl-2 family. In the present study, we investigated the role of microRNA-181a in the apoptosis of tubular epithelial cell induced by DDP.

Methods  HK-2 cells were cultured, transfected with microRNA-181a inhibitor for 48 hours, and stimulated with 50 µmol/L cisplatin for 24 hours. MicroRNA-181a expression was analyzed by real time PCR, and cell apoptosis was detected by flow cytometry. Moreover, Bcl-2 and Bcl-2-associated X protein (Bax) expression were measured by Western blotting.

Results  MicroRNA-181a expression significantly down-regulated in cells transfected with microRNA-181a inhibitor, compared with that in untransfectd cells (21.19±2.01 vs. 38.87±1.97, P <0.05). Cell apoptosis induced by DDP significantly decreased in cells transfected with MicroRNA-181a inhibitor. Compared with DDP treated cells alone, Bcl-2 expression strikingly was up-regulated and Bax expression was down-regulated in cells transfected with microRNA-181a inhibitor.

Conclusion  One pathway of DDP induces apoptosis of tubular epithelial cell by suppressing Bcl-2 expression is achieved by regulating the target gene of MicroRNA-181a.

     

Proteomic analysis for detecting serum biomarkers related to smoking in humans

Background  Smoking is the leading cause of death in the world. This study focused on the difference of the serum proteomic profiling between healthy smokers and nonsmokers in order to find smoking-specific serum biomarkers.

Methods  Pattern-based proteomic profiling of 100 serum samples (from 50 Chinese male smokers and 50 matched nonsmokers) was performed through magnetic bead fractionation coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis (MALDI-TOF-MS) and resulting data were statistically analyzed by Ciphergen ProteinChip software 3.0.2.

Results  We found 72 serum peaks were significantly different between smokers and nonsmokers (P <0.05). Marker peaks of mass-to-charge ratio (m/z) 3159.13, 7561.03 and 9407.32 were smoking-specific.

Conclusion  The preliminary data suggested that smoking-specific serum biomarkers could be detected in humans.

     

Epicardial radiofrequency ablation for left ventricular aneurysm related ventricular arrhythmias during off-pump coronary artery bypass surgery

Background  Left ventricular aneurysm (LVA) is one of the serious complications after acute myocardial infarction. We attempted to evaluate the preliminary efficacy of LVA repair combined with epicardial radiofrequency ablation for ventricular arrhythmia during off-pump coronary artery bypass grafting (OPCAB).

Methods  From June 2009 to April 2011, 31 patients with LVA had angina symptoms and ventricular arrhythmia. In all patients, circular and cross-shaped radiofrequency epicardial ablations were performed using unipolar ablation pen along the border between the aneurysm wall and normal cardiac tissue and in the central zone of the aneurysms, followed by a linear placation of ventricular aneurysms on beating heart.

Results  All the patients showed complete recovery. The average number of grafted vessels was 2.7±1.3. Intraoperative examinations revealed that the ventricular arrhythmia was effectively controlled by radiofrequency ablation. All cases had been followed up for one year. Holter monitoring revealed a significant reduction in ventricular arrhythmias (P <0.05). Echocardiography showed significant increase in left ventricular ejection fraction (P <0.05) and decrease in left ventricular end-diastolic diameter (P <0.05).

Conclusions  For patients with ventricular aneurysm and preoperative malignant arrhythmia, aneurysm repair plus epicardial radiofrequency ablation in OPCAB was found to be an effective and feasible therapeutic technique. However, medium- to long-term therapeutic efficacy of this method remains to be determined by future studies and observations.

     

Effect of peritumoral injection of boanmycin hydrochloride within temperature-sensitive in situ gel using Hep-G2 hepatoma nude mice model

Background  Boanmycin hydrochloride, a new antitumor agent, has a short half-life and fast clearance speed in vivo. The aim of this research was to investigate the effectiveness of peritumor injection of boanmycin hydrochloride within temperature-sensitive gel in situ using Hep-G2 hepatoma nude mice model.

Methods  Nude mice with human Hep-G2 tumor in right flank were randomly divided into four groups: normal saline group, in situ gel only group, boanmycin hydrochloride in situ saline group, and boanmycin hydrochloride in situ gel group, and were treated with injection of corresponding agents into peripheral tissue of the tumor. The volume of the tumor and the body weight of the mice were regularly measured, and tumor growth curve was generated. The size, internal echo, and blood flow of the tumors were observed by color Doppler ultrasonography. Histopathologic changes of the tumor after treatment were observed under both optical and transmission electron microscopy.

Results  The tumor growth was significantly inhibited by peritumoral therapy in boanmycin hydrochloride in situ gel group with the tumor inhibitory rate of 86.76%. The blood flow of the tumor was still seen in both normal saline group and in situ gel only group on color Doppler ultrasound. Punctate calcification and dotted blood flow were seen in boanmycin hydrochloride group; however, there was massive calcification and no blood flow in the tumor in the boanmycin hydrochloride in situ gel group. Large areas of necrosis and apoptotic cells were shown by microscopic observation in boanmycin hydrochloride in situ gel group.

Conclusion  Temperature-sensitive boanmycin hydrochloride in situ gel can effectively delay the release of boanmycin hydrochloride and increase its anticancer effects for liver cancer in animal model.

     

Serum major-histocompatibility-complex class I-related chain A antibody detection for the evaluation of graft dysfunction in renal allograft recipients

Background  In addition to the well-known antibodies against human leukocyte antigens (HLA)-induced kidney-graft rejection, polymorphic major-histocompatibility-complex (MHC) class I-related chain A (MICA) antigens can elicit antibodies and have been suggested to play a role in the antibody-mediated allograft rejection (AMR). We carried out a prospective study of MICA antibodies in post-renal transplant patients to determine the association between MICA antibodies, C4d staining, histological features, and graft outcome.

Methods  We tested 52 patients who had biopsy results due to graft dysfunction. The MICA antibodies in concurrent sera were determined by Luminex. All patients were followed up for one year after renal biopsy. The influence of antibody production on the function of graft was analyzed.

Results  Antibodies against MICA were positive in 15 out of the 52 patients (28.9%). The presence of MICA antibodies was associated with renal-allograft deterioration. During one-year follow-up, the estimated glomerular filtration rate (eGFR) decreased (24.0±3.4)% among recipients with anti-MICA antibodies. However, among recipients without anti-MICA antibodies, the eGFR has declined only (8.4±3.0)% (P=0.017). The association between C4d staining, histological features and MICA antibody production was found no significant difference.

Conclusion  Besides anti-HLA antibodies, the presence of post-transplant MICA antibody is associated with poor graft outcome and increases the risk of graft failure.

     

Anteroapical aneurysm plication improves mechanical intraventricular dyssynchrony in patients with anterior myocardial infarction

Background  Left ventricular (LV) dyssynchrony has been described to occur in patients with myocardial infarction. Dyssynchrony of left ventricular mechanical contraction produces adverse hemodynamic consequences. This study aimed to test the capacity of geometric rebuilding by aneurysm plication to restore a more synchronous contractile pattern after a mechanical, rather than electrical, intervention.

Methods  A total of sixty patients with anterior myocardial infarction, QRS duration <120 ms, electively undergoing operation between January 2008 and January 2010 were included for analysis. Real-time 3-dimensional echocardiography was performed to assess LV function, LV systolic and diastolic dyssynchrony by measuring ejection fraction (EF), peak ejection rate (PER), peak filling rate (PFR) and LV dyssynchrony. LV dyssynchrony was defined as the systolic dyssynchrony of the time to reach the minimum systolic volume for 16 LV segments, expressed in percent cardiac cycle, systolic dyssynchrony index (SDI). We compared changes of LV dyssynchrony at different interval times.

Results  LV contraction was significantly asynchronous because preoperative SDI was higher, EF, PER and PFR were lowered. Compared with function after operation, LV mechanical intraventricular resynchronization was improved with decreased SDI ((8.7±0.5) % vs. (14.3±1.6) %, P=0.01); LV function was improved with EF increasing ((43±9)% vs. (37±7)%, P=0.001), and LV systolic and diastolic dyssynchrony was improved with more rapid PFR (199.4±15.6 vs. 148.4±21.2, P=0.002) and PER (212.4±14.5 vs. 156.3±26.2, P=0.001).

Conclusions  Systolic and diastolic dyssynchrony was highly prevalent in patients with aneurysm, irrespective of QRS duration. Aneurysm plication produces a mechanical intraventricular resynchronization.

     

Reversal of multidrug resistance in renal cell carcinoma by short hairpin RNA targeting MDR1 gene

Background  Over-expression of P-glycoprotein (P-gp), encoded by the MDR1 gene, confers multidrug resistance (MDR) in renal cell carcinoma (RCC) and is a major reason for unsuccessful chemotherapy. This study aimed to determine the effct of RNA interference (RNAi) on the reversal of MDR in human RCC.

Methods  We designed and selected one short hairpin RNA (shRNA) targeting MDR1 gene, which is stably expressed from integrated plasmid and transfected by lentivirus fluid in human RCC A498 cell.

Results  The MDR1-targeted RNAi resulted in decreased MDR1 gene mRNA level (P <0.001), almost abolished P-gp expression and reversed MDR to different chemotherapy drugs in the RCC A498 cell line.

Conclusion  MDR could be reversed by RNAi in human RCC A498 cell line, which may be used for clinical application in future.

     

Mammalian target of rapamycin inhibitor abrogates abnormal osteoclastogenesis in neurofibromatosis type 1

Background Neurofibromatosis type 1 (NF1) is the most common genetic syndrome predisposing patients to various tumors due to dysregulation of the Ras signaling pathway.Recent research has shown NF1 pat...     

Gene delivery in peritoneal dialysis related peritoneal fibrosis research

Objective  To summarize the development of gene delivery vectors in peritoneal fibrosis research and discuss the feasibility and superiority of lentiviral vectors.

Data sources  The data in this article were collected from PubMed database with relevant English articles published from 1995 to 2011.

Study selection  Articles regarding the gene therapy in peritoneal fibrosis research using non-viral vectors, adenoviral vectors, retroviral vectors, and lentiviral vectors were selected. Data were mainly extracted from 60 articles, which are listed in the reference section of this review.

Results  Non-viral vector-mediated gene delivery (including naked DNA for ex vivo, oligonucleotides, ultrasound- contrast agent mediated naked gene delivery, etc.) and viral vector-mediated gene delivery (including adenovirus, helper-dependant adenovirus, and retrovirus vectors) have been successfully applied both in the mechanistic investigation and the potential prevention and treatment of peritoneal fibrosis.

Conclusions  Peritoneal fibrosis is a major complication of peritoneal dialysis (PD). Recently, the wide use of the gene delivery technique made it possible to access and further research peritoneal fibrosis. The use of lentiviral vector is expected to be widely used in PD research in the future due to its advantages in gene delivery.

     

Thiopurine methyltransferase gene polymorphisms and activity in Chinese patients with inflammatory bowel disease treated with azathioprine

Background  The thiopurine drugs are well established in the treatment of inflammatory bowel disease (IBD). However, uncertainty regarding the risk for neutropenia and hepatotoxicity deters its using. Thiopurine methyltransferase (TPMT) is the key enzyme in the metabolism of thiopurine. The aim of this study was to investigate the association of TPMT polymorphisms and activity with azathioprine (AZA)-related adverse events and clinical efficacy in Chinese Han patients with IBD.

Methods  Fifty-two Han IBD patients treated with AZA were assessed for TPMT*2, *3A, *3B, and *3C, and for adverse events. Then, using reverse-phase high-performance liquid chromatography, TPMT activity was measured in 13 patients to analyze its correlation with AZA-related toxicity and clinical efficacy.

Results  Of the 52 patients, five experienced myelotoxicity and one experienced hepatotoxicity during treatment. No TPMT*2, *3A, *3B or *3C polymorphisms were detected in any of the 52 patients. In the 13 patients with TPMT activity measurement, TPMT activity ranged from 7.2 to 28.8 U/ml packed red blood cells (pRBCs). Among the 5 patients who suffered from myelotoxicity, 3 were affected in the early stage of AZA therapy. In these 3 patients, TPMT levels were significantly lower than those in patients without myelotoxicity, which reached statistical significance ((9.3±2.1) U/ml pRBC vs. (18.0±6.2) U/ml pRBC; P=0.046). One patient who had higher TPMT activity (28.8 U/ml pRBC) suffered from hepatotoxicity during AZA therapy. Patients who achieved a clinical response had lower TPMT activity than those failed to respond ((13.7±3.5) U/ml pRBC vs. (22.0±5.5) U/ml pRBC; P=0.009).

Conclusions  TPMT variants do not completely account for the AZA-related myelotoxicity in Chinese Han IBD patients. However, measurement of TPMT activity may be helpful in reducing the risk of toxicity, and predicting the therapeutic efficacy.