Efficacy and safety of secukinumab in patients with psoriatic arthritis: A meta-analysis of different dosing regimens.

The appropriate dosing regimens of secukinumab for psoriatic arthritis (PsA) are not well defined. We performed a meta-analysis to evaluate the efficacy and safety of different dosing regimens of secukinumab in the treatment of PsA. A systematic search was conducted using major electronic databases to identify relevant randomized controlled trials (RCTs) comparing secukinumab 300 mg versus secukinumab 150 mg in patients with PsA. Meta-analysis was performed using Review Manager software (version 5.3). Six studies with a total of 1141 patients were included. At week 24, secukinumab 300 mg was associated with a higher American College of Rheumatology 20% response (ACR 20), ACR 50, PASI 75 response rate, and dactylitis resolution rate than secukinumab 150 mg, especially in the anti-TNF-IR subgroup. At week 52, secukinumab 300 mg was associated with a higher psoriasis area and severity index (PASI) 75 and PASI 90 response rate than secukinumab 150 mg. There was no significant difference between secukinumab 300 mg and secukinumab 150 mg in the risk of any adverse events (AEs) and serious AEs at either week 24 or week 52. Secukinumab 300 mg was significantly more effective than 150 mg, especially for patients with PsA who have failed TNF therapy, and it was well tolerated.

Efficacy and safety of secukinumab in patients with psoriatic arthritis: A meta-analysis of different dosing regimens

The appropriate dosing regimens of secukinumab for psoriatic arthritis (PsA) are not well defined. We performed a meta-analysis to evaluate the efficacy and safety of different dosing regimens of secukinumab in the treatment of PsA. A systematic search was conducted using major electronic databases to identify relevant randomized controlled trials (RCTs) comparing secukinumab 300 mg versus secukinumab 150 mg in patients with PsA. Meta-analysis was performed using Review Manager software (version 5.3). Six studies with a total of 1141 patients were included. At week 24, secukinumab 300 mg was associated with a higher American College of Rheumatology 20% response (ACR 20), ACR 50, PASI 75 response rate, and dactylitis resolution rate than secukinumab 150 mg, especially in the anti-TNF-IR subgroup. At week 52, secukinumab 300 mg was associated with a higher psoriasis area and severity index (PASI) 75 and PASI 90 response rate than secukinumab 150 mg. There was no significant difference between secukinumab 300 mg and secukinumab 150 mg in the risk of any adverse events (AEs) and serious AEs at either week 24 or week 52. Secukinumab 300 mg was significantly more effective than 150 mg, especially for patients with PsA who have failed TNF therapy, and it was well tolerated.

Evidence of motor injury due to damaged corticospinal tract following acute hemorrhage in the basal ganglia region.

The integrity of the corticospinal tract (CST) is significantly affected following basal ganglia haemorrhage. We aimed to assess the local features of CST and to effectively predict motor function by diffusion characteristics of CST in patients with motor injury following acute haemorrhage in the acute basal ganglia region. We recruited 37 patients with paresis of the lateral limbs caused by acute basal ganglia haemorrhage. Based on the automated fiber quantification method to track CST, assessed the character of each CST segment between the affected and contralateral sides, and correlated these with the Fugl-Meyer (FM) and Barthel Index (BI) scores at 6 months after onset. The fractional anisotropy (FA) values of the injured side of CST showed a significantly lower FA than the contralateral side along the tract profiles (p < 0.05, corrections for multiple comparisons). The FA values of each site at the internal capsule, closed corona radiata were positively correlated with the FM and BI score at 6 months after onset (p < 0.001, respectively). Our findings assessed the character of CST vividly in detail and dementated the primary sites of CST can predict the long-term outcome of motor function. This study may facilitate future clinical and cognitive studies of acute haemorrhage.

Polymyxin monotherapy versus polymyxin-based combination therapy against carbapenem-resistant Klebsiella pneumoniae: A systematic review and meta-analysis.

OBJECTIVES: This meta-analysis was performed to compare polymyxin monotherapy and polymyxin-based combination therapy for carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections. METHODS: We conducted searches on MEDLINE, Embase and Cochrane Collaborative database for both observational studies and randomised controlled trials (RCTs) comparing polymyxin monotherapy with polymyxin-based combination therapy in patients with CR-KP infection. The primary outcome was mortality. We divided all included studies into several groups according to different combination-combination and different infection types. The odds ratio (OR) and 95% confidence intervals (CI) were calculated for outcome analysis. RESULTS: Ten studies with 481 patients were included. Polymyxin monotherapy was associated with higher mortality than polymyxin-based combination therapy in treatment of CR-KP bloodstream infections (BSI) (OR 1.93, 95% CI 1.14-3.27, P = 0.01) and ventilator-associated pneumonia (VAP)/hospital-acquired pneumonia (HAP) (OR 3.82, 95% CI 1.15-12.71, P = 0.03). In subgroup analysis of different combinations, mortality was significantly higher with polymyxin monotherapy compared with combination therapy with tigecycline (OR 1.88, 95% CI 1.05-3.37, P = 0.03), or with cabapenem (OR 3.11, 95% CI 1.25-7.74, P = 0.01), but no differences were found in combinations with aminoglycosides (OR 1.29, 95% CI 0.72-2.29, P = 0.38). Three-drug combination therapy including polymyxin was also associated with significant survival benefit (OR 3.86, 95% CI 1.60-9.32, P = 0.003). CONCLUSIONS: Polymyxin-based combination therapy provides significant survival benefit in treatment of CR-KP, which appears to be more pronounced when a carbapenem or tigecycline is included in the regimen.

[Study on Flk1+ Cells during Mouse Early Embryogenesis by Lineage Tracing].

OBJECTIVE: To understand the differentiation of mesoderm-derived Flk1+ cells on different locations of the early mouse embryonic development and to explore the potential of Flk1+ cells to differentiate into mesenchymal lineage, like pericytes during vascular development. METHODS: Based on the Cre-LoxP system conditional knockout study strategy, the Flk1-Cre mice and ROSA26 reporter mice were used for lineage-tracing studies. The fate of the Flk1+ progenitor cells was traced with the GFP+ population. The detection of mesoderm marker Flk1, hematopoietic cell-specific marker CD45, endothelial cell-specific markers CD31, CD144, and Emcn (endomucin), pericyte specific markers PDGFRß and NG2, using the methods of immunohistochemistry, immunofluorescence, and flow cytometry should be combined to solve the concerned problems. RESULTS: Immunohistochemical staining of different fractions of E8.5-10.5 in the early embryogenesis of Flk1-Cre; ROSA26-EYFP mouse lineage showed that there were multiple populations in the Flk1+ cell-derived GFP+ population surrounding hematopoietic sites, such as dorsal aortas, limb buds and yolk sac. In addition to hematopoietic cells, the CD31+/Emcn+ typical endothelial cells distributed specifically along the blood vessel wall, there were many types of cell populations, such as mesenchymal-like cells. The immunofluorescence demonstrated that the cells of this group are neither hematopoietic, non-endothelial cells around the blood vessels, which are NG2+ pericytes. FACS analysis also confirmed that Flk1+ cells contributed to pericytes. In addition, in different hematopoietic sites of the embryo, a small population of CD31+CD140B+ cell populations with a mesenchymal-like morphology was observed in the GFP+ population. CONCLUSION: In the early stages of embryogenesis, mesoderm-derived Flk1+ populations not only contribute to hematopoietic, endothelial, and muscle lineages, but also have a differentiation potential for mesenchymal lineage, like pericytes. The presumably observed CD31+CD140B+ cell population may be a group of endothelial cells differentiated from Flk1+ progenitor cells and undergoing an endothelium-to-mesenchymal transition, EndMT, gradually losing the endothelial surface-specific marker and also starting to express a pericyte surface-specific marker.

Meta-analysis of IL-17 inhibitors in two populations of rheumatoid arthritis patients: biologic-naïve or tumor necrosis factor inhibitor inadequate responders.

OBJECTIVES: To evaluate the efficacy and safety of interleukin 17 (IL-17) inhibitors in two rheumatoid arthritis (RA) populations: biologic-naïve or tumor necrosis factor inhibitor inadequate responders (TNF-IR). METHOD: A systematic search was performed in major electronic databases to identify relevant randomized controlled trials (RCTs) reporting the American College of Rheumatology 20% (ACR20), ACR50, ACR70 responses and adverse events (AEs) of IL-17 inhibitors versus placebo in patients with RA. We divided these patients into two subgroups: biologic-naïve or TNF-IR. The meta-analysis was performed using Review Manager 5.3 software. Results were expressed as risk ratio (RR) with pertinent 95% confidence interval (95% CI). RESULTS: Ten studies with a total of 2499 patients were included. For biologic-naïve patients, ACR50 and ACR70 responses were significantly better with IL-17 inhibitors than placebo (RR = 1.71, 95% CI 1.23-2.38, P = 0.001 and RR = 2.63, 95% CI 1.10-6.25, P = 0.03, respectively), but ACR20 responses for IL-17 inhibitors were not statistically superior to placebo (RR = 1.34, 95% CI 0.94-1.91, P = 0.11). For TNF-IR, IL-17 inhibitors were effective in achieving ACR20 (RR = 1.67, 95% CI 1.40-2.00, P < 0.00001), ACR50 (RR = 1.94, 95% CI 1.43-2.63, P < 0.0001), and ACR70 (RR = 2.11, 95% CI 1.26-3.55, P = 0.005) compared to placebo. In the safety analysis, IL-17 inhibitors did not show increased risk of any AEs by comparing to placebo in both biologic-naïve patients and TNF-IR. CONCLUSION: IL-17 inhibitors were effective in the treatment of RA without increased risk of AEs, whether for biologic-naïve patients or TNF-IR. Key Points • In this meta-analysis comparing IL-17 inhibitors with placebo in 2499 rheumatoid arthritis patients, IL-17 inhibitors improved ACR50 and ACR70, but not ACR20, responses in biologic-naïve patients. • IL-17 inhibitors improved ACR20, ACR50, and ACR70 responses in tumor necrosis factor inhibitor inadequate responders.

[Protective effect of raspberry extract on ConA-induced acute liver injuryin mice].

In this experiment,the antioxidant capacity of raspberry extract and the protective effect on liver injury induced by ConA in mice were investigated. Balb/C male mice were randomly divided into six groups: normal group,model group,bicyclol control group( 200 mg·kg~(-1)),low-dose raspberry extract group( 200 mg·kg~(-1)),middle-dose raspberry extract group( 400 mg·kg~(-1)),and highdose raspberry extract group( 800 mg·kg~(-1)). Each group was intragastrically administered with drugs according to the body weight once a day. Seven days later,all of the groups except for the normal group were treated with ConA( 20 mg·kg~(-1)) through tail vein injection to establish the acute liver injury model. The mice were put to death 8 hours later. The organ indexes were calculated. These rum levels of ALT,AST and LDH and the activities of SOD,CAT,GSH and MDA in liver tissue were detected. HE staining was used to observe the pathological changes of liver tissue in mice. Western blot was used to detect the expressions of Bax,Bcl-2,Nrf2 and Keap-1. The antioxidant capacity of raspberry extract was measured by CAA assay. The results showed that,raspberry extract had a strong antioxidant capacity. Simultaneously,compared with the model group,raspberry extract can significantly improve the pathological conditions of liver,and significantly reduce ALT,AST and LDH activities in serum of liver injury mice( P<0. 01). The activities of SOD,CAT in liver homogenate supernatant were significantly increased in the high-dose group,the content of GSH increased,while the content of MDA was sharply declined in the high-dose group( P<0. 01). Meanwhile,raspberry extract down-regulated the expressions of Bax and Keap-1 and up-regulated the expressions of Bcl-2 and Nrf2. CAA showed that the compound raspberry extract had a strong antioxidant capacity. Therefore,raspberry extract has an obvious protective effect on acute liver injury induced by ConA in mice.

Sulfonyl-containing phenyl-pyrrolyl pentane analogues: Novel non-secosteroidal vitamin D receptor modulators with favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity.

Modulating the vitamin D receptor (VDR) is an effective way to treat for cancer. We previously reported a potent non-secosteroidal VDR modulator (sw-22) with modest anti-tumor activity, which could be due to its undesirable physicochemical and pharmacokinetic properties. In this study, we investigated the structure-activity and structure-property relationships around the 2'-hydroxyl group of sw-22 to improve the physicochemical properties, pharmacokinetic properties and anti-tumor activity. Compounds 19a and 27b, the potent non-secosteroidal VDR modulators, were identified as the most effective molecules in inhibiting the proliferation of three cancer cell lines, particularly breast cancer cells, with a low IC50 via the distribution of cell cycle and induction of apoptosis by stimulating the expression of p21, p27 and Bax. Further investigation revealed that 19a and 27b possessed favorable rat microsomal metabolic stability (2.22 and 2.3 times, respectively, more stable than sw-22), solubility (43.9 and 50.2 times, respectively, more soluble than sw-22) and in vivo pharmacokinetic properties. In addition, 19a and 27b showed excellent in vivo anti-tumor activity without cause hypercalcemia, which is the main side effect of marketed VDR modulators. In summary, the favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity of 19a and 27b highlight their potential therapeutic applications in cancer treatment.

Efficacy of Xuebijing for coagulopathy in patients with sepsis.

OBJECTIVES: To provide evidence of the clinical efficacy of Xuebijing (XBJ) on blood coagulation in patients with sepsis. METHODS: We conducted this meta-analysis in The People's Hospital of Liaoning Province, Shenyang, China between December 2013 and May 2014. We searched a number of databases for relevant randomized controlled trials (RCTs) published before December 2013 using the keywords 'Xuebijing', 'coagulation' and 'sepsis'. Statistical analysis was performed with Review Manager 5.2 from the Cochrane Collaboration. RESULTS: Fourteen RCTs involving 867 patients were included. Compared with placebo, XBJ injection significantly improved platelets (mean differences [MD] = 42.14, 95% confidence interval [CI]: 22.42 - 61.86, p<0.00001), shortened the activated partial thromboplastin time (MD = -4.81, 95% CI: -7.86 - [-1.76], p=0.002), shortened the prothrombin time (MD = -2.33, 95% CI: -4.15 - [-0.51], p=0.01), and shortened the thrombin time (MD = -2.05, 95% CI: -3.52 - [-0.58], p=0.006). However, no significant difference was found between the XBJ injection and the placebo group for fibrinogen (MD = 0.21, 95% CI: -0.38 - 0.81, p=0.48). CONCLUSION: Xuebijing injection may improve coagulopathy in patients with sepsis. High-quality and large sample clinical trials are needed for confirmation.

[Effect of bortezomib on sensitization of HL-60 cells to TRAIL].

This study was aimed to explore whether bortezomib can sensitize HL-60 cells to TNF-related apoptosis-inducing ligand (TRAIL) and to investigate its possible mechanism. The HL-60 cells were treated by different concentrations of TRAIL combined with subtoxic concentration of bortezomib. The proliferative inhibition of treated HL-60 cell was analysed by MTT assay. The cell apoptosis was determined by flow cytometry with Annexin V/PI double staining and the expression of caspase-8 was detected by Western blot. The results showed that the subtoxic concentration of bortezomib combined with 10 ng/ml of TRAIL enhanced apoptosis of HL-60 cells, as compared with TRAIL used alone; the expression of caspase-8 increased correspondingly. It is concluded that subtoxic concentration of bortezomib can sensitize HL-60 cells to TRAIL and its mechanism may be related to upregulation of caspase-8 expression.