Fibroblast growth factor 2 modulates extracellular purine metabolism by upregulating ecto-5′-nucleotidase and adenosine deaminase in cultured rat spinal cord astrocytes

Purinergic signaling via ATP and adenosine produced by astrocytes is one pathway underlying neuron–glia interactions in the central nervous system (CNS). In production of purines, extracellular metabolism of released purines via ecto-enzymes is important. The expression and activities of these enzymes are altered under pathological conditions. Production of fibroblast growth factor 2 (FGF2) is increased under pathological conditions, and this has various effects on astrocytes. Here, we investigated the effects of FGF2 on purine metabolism in cultured rat spinal cord astrocytes. Astrocytes rapidly metabolized purines added to the extracellular solution. FGF2 increased extracellular metabolism of AMP to adenosine and of adenosine to inosine by upregulating ecto-5′-nucleotidase and adenosine deaminase (ADA), respectively. ADA activity and protein were detected both in the cytosol and external solution of astrocytes, and their levels were markedly increased by FGF2. FGF2 also increased metabolism of endogenously released ATP, resulting in a transient increase in adenosine and substantial accumulation of extracellular inosine. Moreover, FGF2 increased ATP release by upregulating the activity of gap junction hemichannels. These data show that FGF2 regulates purine production in astrocytes and suggest that extracellular ADA released by astrocytes plays an important role in extracellular purine metabolism in the CNS.     

Prognostic impact of lipid contents on the target lesion in patients with drug eluting stent implantation

We sought to determine the morphologic predictors of major adverse cardiac events (MACEs) after successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES), using integrated backscatter intravascular ultrasound (IB-IVUS). Conventional IVUS and IB-IVUS were performed in 260 consecutive patients who underwent PCI with DES. Three-dimensional analyses were performed to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcification). Patients were divided into two groups according to the median lipid volume (LV) in the target lesion. MACEs were defined as death, nonfatal myocardial infarction, and any repeat revascularization. The median follow-up interval was 1285 days. MACEs were observed in 64 patients (24.6 %). Patients having a larger LV compared with their counterparts had worse long-term clinical outcomes regarding mortality (3.8 vs. 0 %, P = 0.02) and MACEs (31.5 vs. 17.7 %, P = 0.008) by log-rank test. After adjustment for confounders, large LV (odds ratio 1.95, 95 % confidence interval 1.14–3.33, P = 0.02) was significantly and independently associated with MACEs. The assessment of coronary plaque characteristics in the target lesion may be useful to predict long-term outcome following successful coronary intervention.     

Proposal of a Parameter for OATP1B1 Inhibition Screening at the Early Drug Discovery Stage

It is known that potent inhibition of organic-anion-transporting polypeptide (OATP)1B1 increases exposure to statins, leading to severe adverse effects. The aim of this study was to propose a parameter and its criteria in OATP1B1 inhibition assay at the early drug discovery stage to avoid compounds with the risk of statin-related adverse effects. According to drug label information, most compounds classified as “contraindicated” or “should be avoided” when administered concomitantly with statins increased their AUCs more than 4-fold. Generally, R values where R = 1 + plasma unbound fraction (fu) × maximum inhibitor concentration at the inlet to the liver/IC₅₀ are used to evaluate the extent of clinical drug interaction. However, clinical doses and C_max cannot be determined at the screening stage. Therefore, we estimated the correlations between change in AUC of statins concomitantly administered with OATP1B1 inhibitors and various parameters including fu/IC₅₀. Cyclosporin A, rifampicin, and telaprevir increased the AUC of statins more than 4-fold and fu/IC₅₀ of these compounds was >0.1 L/μmol. On the other hand, fu/IC₅₀ of other compounds was ≤0.03 L/μmol. This study indicates that fu/IC₅₀ is a useful parameter to avoid compounds that seriously affect statin potency through interaction with OATP1B1 at the screening stage.     

Benefits of robotically-assisted surgery for complex mitral valve repair

OBJECTIVESTo determine whether robotic mitral valve repair can be applied to more complex lesions compared with minimally invasive direct mitral valve repair through a right thoracotomy. Open in a separate windowMETHODSWe enrolled 335 patients over a 9-year period; 95% of the robotic surgeries were performed after experience performing direct mitral valve repair.RESULTSThe mean age in the robotic versus thoracotomy repair groups was 61 ± 14 vs 55 ± 11 years, respectively (P < 0.001); 97% vs 100% of the patients, respectively, had degenerative aetiologies. Repair complexity was simple in 106 (63%) vs 140 (84%), complex in 34 (20%) vs 20 (12%) and most complex in 29 (17%) vs 6 (4%) patients undergoing robotic versus thoracotomy repair, respectively. The average complexity score with robotic repair was significantly higher versus thoracotomy repair (P < 0.001). The robotic group underwent more chordal replacement using polytetrafluoroethylene and less resections. All patients underwent ring annuloplasty. Cross-clamp time did not differ between the groups, and no strokes or deaths occurred. More patients undergoing robotic repair underwent concomitant procedures versus the thoracotomy group (30% vs 14%, respectively; P < 0.001). The overall repair rate was 100%, with no early mortality or strokes in either group. Postoperative mean residual mitral regurgitation was 0.3 in both groups, and the mean pressure gradient through the mitral valve was 2.4 vs 2.7 mmHg (robotic versus thoracotomy repair, respectively; P = 0.031).CONCLUSIONSRobotic surgery can be applied to repair more complex mitral lesions, with excellent early outcomes.     

Rapid decrease in serum VEGF-A levels may be a worse prognostic biomarker for patients with platinum-resistant recurrent ovarian cancer treated with bevacizumab and gemcitabine

The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome. Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups—patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with < 50% decrease serum VEGF-A levels (Group B). The association between clinical outcome and serum VEGF levels was investigated between the two groups. Among 18 patients, 10 were in Group A and 8 in Group B. Group A exhibited a lower response rate (0% vs.75% p < 0.01) and clinical benefit rate (60% vs.100% p = 0.02) than Group B. The median serum VEGF-A level of Group A before the first cycle of Bev-Gem therapy was higher than that in Group B (61.2 vs. 3.7 pg/mL, p < 0.01). Group A exhibited worse PFS (7 vs., 10 months, p < 0.01) and OS (17 vs. 26 months, p = 0.04) than Group B. There were more patients with > 10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01). The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results.