The regenerative potential of c‐kit+ cardiac stem cells (CSCs) is severely limited by the poor survival of cells after transplantation in the infarcted heart. We have previously demonstrated that preconditioning human CSCs (hCSCs) with the heme oxygenase‐1 inducer, cobalt protoporphyrin (CoPP), has significant cytoprotective effects in vitro. Here, we examined whether preconditioning hCSCs with CoPP enhances CSC survival and improves cardiac function after transplantation in a model of myocardial infarction induced by a 45‐minute coronary occlusion and 35‐day reperfusion in immunodeficient mice. At 30 minutes of reperfusion, CoPP‐preconditioned hCSCsGFP+, hCSCsGFP+, or medium were injected into the border zone. Quantitative analysis with real‐time qPCR for the expression of the human‐specific gene HLA revealed that the number of survived hCSCs was significantly greater in the preconditioned‐hCSC group at 24 hours and 7 and 35 days compared with the hCSC group. Coimmunostaining of tissue sections for both green fluorescent protein (GFP) and human nuclear antigen further confirmed greater hCSC numbers at 35 days in the preconditioned‐hCSC group. At 35 days, compared with the hCSC group, the preconditioned‐hCSC group exhibited increased positive and negative left ventricular (LV) dP/dt, end‐systolic elastance, and anterior wall/apical strain rate (although ejection fraction was similar), reduced LV remodeling, and increased proliferation of transplanted cells and of cells apparently committed to cardiac lineage. In conclusion, CoPP‐preconditioning of hCSCs enhances their survival and/or proliferation, promotes greater proliferation of cells expressing cardiac markers, and results in greater improvement in LV remodeling and in indices of cardiac function after infarction. Stem Cells
Heart failure; Myocardial infarction; Human cardiac stem cell; Cell survival; Preconditioning; HO‐1 inducer; Cobalt protoporphyrin
The regenerative potential of c-kit+ cardiac stem cells (CSCs) is severely limited by the poor survival of cells after transplantation in the infarcted heart. We have previously demonstrated that preconditioning human CSCs (hCSCs) with the heme oxygenase-1 inducer, cobalt protoporphyrin (CoPP), has significant cytoprotective effects in vitro. Here, we examined whether preconditioning hCSCs with CoPP enhances CSC survival and improves cardiac function after transplantation in a model of myocardial infarction induced by a 45-minute coronary occlusion and 35-day reperfusion in immunodeficient mice. At 30 minutes of reperfusion, CoPP-preconditioned hCSCsGFP+, hCSCsGFP+, or medium were injected into the border zone. Quantitative analysis with real-time qPCR for the expression of the human-specific gene HLA revealed that the number of survived hCSCs was significantly greater in the preconditioned-hCSC group at 24 hours and 7 and 35 days compared with the hCSC group. Coimmunostaining of tissue sections for both green fluorescent protein (GFP) and human nuclear antigen further confirmed greater hCSC numbers at 35 days in the preconditioned-hCSC group. At 35 days, compared with the hCSC group, the preconditioned-hCSC group exhibited increased positive and negative left ventricular (LV) dP/dt, end-systolic elastance, and anterior wall/apical strain rate (although ejection fraction was similar), reduced LV remodeling, and increased proliferation of transplanted cells and of cells apparently committed to cardiac lineage. In conclusion, CoPP-preconditioning of hCSCs enhances their survival and/or proliferation, promotes greater proliferation of cells expressing cardiac markers, and results in greater improvement in LV remodeling and in indices of cardiac function after infarction.
Heart failure; Myocardial infarction; Human cardiac stem cell; Cell survival; Preconditioning; HO-1 inducer; Cobalt protoporphyrin
OBJECTIVE: Gliomas are characterized by its local invasiveness and poor prognosis. It has been demonstrated that the survival benefit is associated with the extent of surgical resection. But it is difficult to distinguish tumor margins due to the infiltrative nature, and gliomas often recur within 2-3 cm from the borders of the resection cavity. Recently, fluorescence-guided resection has been demonstrated to improve discrimination of tumor tissue and increase the extent of surgical resection. However, insufficient protoporphyrin IX accumulation may limit the benefits of FGR in low-grade glioma and the marginal area. METHODS: We investigated the expression of the ATP-binding cassette transporter ABCB6 in gliomas, and the correlation between ABCB6 expression and PpIX accumulation. Meanwhile, Glioma cells and astrocytes were preconditioned with calcitriol or arsenic trioxide. Changes in ALA-induced PpIX fluorescence were assessed by flow cytometry and fluorescence microscopy. Furthermore, expression of porphyrin synthetic enzymes in pretreated glioma cells was analyzed. RESULTS: The expression levels of ABCB6 significantly elevated in gliomas, A previously finding was the fact that ABCB6 mRNA expression in solidly fluorescing tumor tissues was significantly higher than that in vaguely fluorescing tumors, Accordingly, ABCB6 overexpression in cell lines increased ALA-induced PpIX accumulation and fluorescent quality. Meanwhile, calcitriol or arsenic trioxide can be administered prior to ALA as a non-toxic preconditioning regimen to significantly enhance ALA- induced PpIX levels and fluorescence. This increase in PpIX level was detected preferentially in glioma versus normal cells. Moreover, mechanistic studies documented that expression of the porphyrin synthesis enzymes coproporphyrinogen oxidase was increased by calcitriol or arsenic trioxide at the mRNA level. CONCLUSIONS: ABCB6 overexpression is a potential approach to enhance accumulation of PpIX for optimising the subjective discrimination of vague fluorescence. We demonstrated for the first time a simple, non-toxic and highly effective preconditioning regimen to selectively enhance PpIX fluorescence in glioma cells.
No data on the incidence of pleural effusion (PE) in Chinese patients with pulmonary embolism are available to date. The aim of the current study was to investigate the frequency of PE in a Chinese population of patients with pulmonary embolism.
This was a retrospective observational single-center study. All data of computed tomography pulmonary angiography (CTPA) performed over 6-year period on adult patients with clinically suspected pulmonary embolism were analyzed.
From January 2008 until December 2013, PE was identified in 423 of 3141 patients (13.5%) with clinically suspected pulmonary embolism who underwent CTPA. The incidence of PE in patients with pulmonary embolism (19.9%) was significantly higher than in those without embolism (9.4%) (P < 0.001). Majority of PEs in pulmonary embolism patients were small to moderate and were unilateral. The locations of emboli and the numbers of arteries involved, CT pulmonary obstruction index, and parenchymal abnormalities at CT were not associated with the development of PE.
PEs are present in about one fifth of a Chinese population of patients with pulmonary embolism, which are usually small, unilateral, and unsuitable for diagnostic thoracentesis.
Computed Tomography Pulmonary Angiography; Pleural Effusion; Pulmonary Embolism
Extensive evidence implicates the Eph receptor family of tyrosine kinases and its ligand, ephrin, in glioma invasion, but it remains incompletely understood how these receptors affect chemotactic behavior of glioma. We sought to identify the Eph family members that correlate with patients' survival and to reveal the function of Eph in glioma invasion.
Clinical relevance of EphB genes was confirmed in a clinically annotated expression data set of 195 brain biopsy specimens. The function of EphB was analyzed in vitro and in vivo.
Levels of mRNA of certain EphB members were significantly different in histological grades of glioma. According to Kaplan–Meier analysis, only the EphB1 level among 5 members of EphB emerged to be a powerful predictor of favorable survival in malignant glioma (n = 97, P = .0048), although the levels of EphB1 expression did not vary across the tumor grades. Immunoprecipitation showed that tyrosine phosphorylated EphB1 was not detected in all glioma cells tested. Forced overexpression and autophosphorylation of EphB1 in low expressor cell lines (U251, U87) did not affect cell migration or invasion in vitro, whereas EphB1 phosphorylation induced by ephrin-B2/Fc significantly decreased migration and invasion. Cells expressing ephrin-B2 showed noteworthy morphological changes consistent with migration induction; this alteration was negated by EphB1 overexpression. Concomitantly, overexpression of EphB1 abrogated the increased migration and invasion induced by ephrin-B2 in vitro and in vivo.
These data suggest that ligand-dependent EphB1 signaling negatively regulates glioma cell invasion, identifying EphB1 as a favorable prognostic factor in malignant glioma.
glioma; invasion; migration; Eph-ephrin; tyrosine kinase
We performed a systematic review and meta-analysis to address the (added) value of intraoperative 5-aminolevulinic acid (5-ALA)-guided resection of high-grade malignant gliomas compared with conventional neuronavigation-guided resection, with respect to diagnostic accuracy, extent of tumor resection, safety, and survival.
Methods and Findings
An electronic database search of Medline, Embase, and the Cochrane Library was undertaken. The review process followed the guidelines of the Cochrane Collaboration. 10 studies matched all selection criteria, and were thus used for qualitative synthesis. 5-ALA-guided resection demonstrated an overall sensitivity of 0.87 (95% confidence interval [CI], 0.81–0.92), specificity of 0.89 (95% CI, 0.79–0.94), positive likelihood ratio (LR) of 7.62 (95% CI, 3.87–15.01), negative LR of 0.14 (95% CI, 0.09–0.23), and diagnostic odds ratio (OR) of 53.06 (95% CI, 18.70–150.51). Summary receiver operating characteristic curves (SROC) showed an area under curve (AUC) of 94%. Contrast-enhancing tumor was completely resected in patients assigned 5-ALA as compared with patients assigned white light. Patients in the 5-ALA group had higher 6-month progression free survival and overall survival than those in the white light group.
Based on available literature, there is level 2 evidence that 5-ALA-guided surgery is more effective than conventional neuronavigation-guided surgery in increasing diagnostic accuracy and extent of tumor resection, enhancing quality of life, or prolonging survival in patients with high-grade malignant gliomas.
Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.
glioblastoma; signaling; proliferation; invasion; angiogenesis; molecular target
In the title molecule, C15H17N3O2S2, the dihedral angle between the naphthalene ring system and the imidazole ring is 89.63 (2)°. The crystal structure is stablized by weak intermolecuar C—H⋯π and N—H⋯π interactions.
p40phox is an important regulatory subunit of NADPH oxidase, but its role in endothelial reactive oxygen species (ROS) production remains unknown.
Methods and Results
Using coronary microvascular endothelial cells isolated from wild-type and p47phox knockout mice, we found that knockout of p47phox increased the level of p40phox expression, whereas depletion of p40phox in wild-type cells increased p47phox expression. In both cases, the basal ROS production (without agonist stimulation) was well preserved. Double knockout of p40phox and p47phox dramatically reduced (≈65%) ROS production and cells started to die. The transcriptional regulation of p40phox and p47phox expressions involves HBP1. p40phox was prephosphorylated in resting cells. PMA stimulation induced p40phox swift dephosphorylation (within 1 minute) in parallel with the start of p47phox phosphorylation. p40phox was then rephosphorylated, and this was accompanied with an increase in ROS production. Depletion of p40phox resulted in ≈67% loss in agonist-induced ROS production despite the presence of p47phox. These were further supported by experiments on mouse aortas stimulated with angiotensin II.
p40phox is prephosphorylated in resting endothelial cells and can compensate p47phox in keeping basal ROS production. Dephosphorylation of p40phox is a prerequisite for agonist-induced p47phox phosphorylation, and p40phox through its dynamic dephosphorylation and rephosphorylation is involved in the regulation of agonist-induced ROS production.
NADPH oxidase; endothelial cells; gene regulation; reactive oxygen species
The pyranyl ring of the title compound, C22H19NO3, adopts a flattened-boat conformation. The dihedral angle between naphthalene and phenyl rings is 78.3 (1)°The molecule also features an intramolecular N—H⋯Ocarbonyl hydrogen bond. Adjacent molecules are linked by an intermolecular N—H⋯Ocarbonyl hydrogen bond, forming a zigzag chain that runs along the c axis.
In the title molecule, C15H15N3O2S, the dihedral angle between the naphthalene ring system and the imidazole ring is 86.1 (2)°. In the crystal structure, weak intermolecular C—H⋯O and C—H⋯N hydrogen bonds, as well as weak C—H⋯π interactions, connect molecules, forming a two-dimensional network.
In the title compound, C19H15N3S·H2O, the benzothiazole ring system forms a dihedral angle of 7.22 (1)° with the benzene ring and the benzene ring forms a dihedral angle of 80.89 (1)° with the pyridine ring. An intramolecular N—H⋯O interaction is present. The crystal structure is stablized by intermolecular O—H⋯N hydrogen bonds, π–π [centroid–centroid distances = 3.782 (1), 3.946 (1) and 3.913 (1) Å] and C—H⋯π interactions, forming a three dimensional-network.
The title compound, C13H10N2S, contains two independent molecules in its asymmetric unit, with slightly different conformations. In one molecule, the dihedral angle between the benzothiazole unit and the benzene ring is 6.73 (1)°, while the corresponding angle in the other molecule is 1.8 (1)°. In the crystal structure, the molecules are linked into layers by N—H⋯N hydrogen bonds.
A new orthorhombic polymorph of terephthalaldehyde, C8H6O2, with a melting point of 372 K, has been obtained by recrystallization from ethanol. At room temperature, the crystals transform into the well known monoclinic form, with a melting point of 389 K. The crystal structure of the monoclinic form involves C—H⋯O hydrogen bonds, but no such bonds are observed in the orthorhombic form. The molecule is planar.
In the title molecule, C13H10N2O, the dihedral angle between the benzoxazole ring system and the benzene ring is 11.8 (1)°. In the crystal structure, molecules are linked by intermolecular N—H⋯N hydrogen bonds and π⋯π interactions [centroid–centroid distance = 3.6560 (15) Å] to form a two-dimensional network.
In the title complex, [Zn(CH3COO)2(C20H14N4)2]·2H2O, the ZnII atom, which lies on a crystallographic twofold axis, is coordinated by two O atoms of two acetate ligands and two N atoms from two 1,3-bis(benzimidazol-2-yl)benzene ligands in a distorted tetrahedral geometry. The complex molecules and solvent water molecules are connected via O—H⋯N, O—H⋯O and N—H⋯O hydrogen bonds, forming a three-dimensional network.