Hepatocyte growth factor gene therapy reduces ventricular arrhythmia in animal models of myocardial ischemia.

It was recently reported that gene therapy using hepatocyte growth factor (HGF) has the potential to preserve cardiac function after myocardial ischemia. We speculated that this HGF gene therapy could also prevent ventricular arrhythmia. To investigate this possibility, we examined the antiarrhythmic effect of HGF gene therapy in rat acute and old myocardial infarction models. Myocardial ischemia was induced by ligation of the left descending coronary artery. Hemagglutinating virus of Japan (HVJ)-coated liposome containing HGF genes were injected directly into the myocardium fourteen days before programmed pacing. Ventricular fibrillation (VF)was induced by programmed pacing. The VF duration was reduced and the VF threshold increased after HGF gene therapy ( p&#60; 0.01). Histological analyses revealed that the number of vessels in the ischemic border zone was greatly increased after HGF gene injection. These findings revealed that HGF gene therapy has an anti-arrhythmic effect after myocardial ischemia.</p

Usefulness of body surface mapping to differentiate patients with Brugada syndrome from patients with asymptomatic Brugada syndrome.

We attempted to determine the usefulness of body surface mapping (BSM) for differentiating patients with Brugada syndrome (BS) from patients with asymptomatic Brugada syndrome (ABS). Electrocardiograms (ECG) and BSM were recorded in 7 patients with BS and 35 patients with ABS. Following the administration of Ic antiarrhythmic drugs, BSM was recorded in 5 patients with BS and 16 patients with ABS. The maximum amplitudes at J0, J20, J40 and J60 were compared between the 2 groups, as were 3-dimensional maps. The maximum amplitudes at J0, J20 and J60 under control conditions were larger in patients with BS than in patients with ABS (P < 0.05). A three-dimensional map of the ST segments under control conditions in patients with BS showed a higher peak of ST elevation in the median precordium compared to that for patients with ABS. Increases in ST elevation at J20, J40 and J60 following drug administration were greater in patients with BS than in patients with ABS (P < 0.05). Evaluation of the change in amplitude of the ST segment at E5 caused by Ic drug administration was also useful for differentiating between the 2 groups. In conclusion, BSM was useful for differentiating patients with BS from those with ABS.</p

Cell viabilities and biodegradation rates of DNA/protamine complexes with two different molecular weights of DNA.

Two types of DNA/protamine complexes were prepared from protamine sulfate and 7000 base pair (bp) DNA or original DNA to investigate the effect of the molecular weight of DNA on zeta potential, cell viability, flowability, soft tissue response, and biodegradation rate. The 7000 bp DNA/protamine complex had a negative charge while the original DNA/protamine complex had a positive charge. The cell viabilities (90.4-106.8%) of these complexes were close to each other. The 7000 bp DNA/protamine complex became a softer dough than that of the original DNA/complex when both were kneaded with water. In vivo, the original DNA/protamine complex showed a milder tissue response. The original DNA/protamine complex almost disappeared 30 days after implantation. The 7000 bp DNA/complex disappeared approximately 2 weeks after implantation and areas where samples were implanted became empty. Thereafter, the empty space was gradually replaced by new soft tissues. The original DNA/protamine complex showed low intercalation and groove binding ratios of daunorubicin hydrochloride. Results indicate that high DNA condensation by cationic protamine protected the penetration of degradation enzymes into these complexes. It was found that a high molecular weight of DNA reduced the biodegradation rate and flowability. This study suggests that DNA/protamine complexes could be candidates for biomaterials that control biodegradation rates and flowability.福岡歯科大学2013年

A nucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106), sensitizes cells to radiation by suppressing BRCA2 expression

<p>Abstract</p> <p>Background</p> <p>A novel anticancer drug 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd, TAS106) has been shown to radiosensitize tumor cells and to improve the therapeutic efficiency of X-irradiation. However, the effect of TAS106 on cellular DNA repair capacity has not been elucidated. Our aim in this study was to examine whether TAS106 modified the repair capacity of DNA double-strand breaks (DSBs) in tumor cells.</p> <p>Methods</p> <p>Various cultured cell lines treated with TAS106 were irradiated and then survival fraction was examined by the clonogenic survival assays. Repair of sublethal damage (SLD), which indicates DSBs repair capacity, was measured as an increase of surviving cells after split dose irradiation with an interval of incubation. To assess the effect of TAS106 on the DSBs repair activity, the time courses of γ-H2AX and 53BP1 foci formation were examined by using immunocytochemistry. The expression of DNA-repair-related proteins was also examined by Western blot analysis and semi-quantitative RT-PCR analysis.</p> <p>Results</p> <p>In clonogenic survival assays, pretreatment of TAS106 showed radiosensitizing effects in various cell lines. TAS106 inhibited SLD repair and delayed the disappearance of γ-H2AX and 53BP1 foci, suggesting that DSB repair occurred in A549 cells. Western blot analysis demonstrated that TAS106 down-regulated the expression of BRCA2 and Rad51, which are known as keys among DNA repair proteins in the homologous recombination (HR) pathway. Although a significant radiosensitizing effect of TAS106 was observed in the parental V79 cells, pretreatment with TAS106 did not induce any radiosensitizing effects in BRCA2-deficient V-C8 cells.</p> <p>Conclusions</p> <p>Our results indicate that TAS106 induces the down-regulation of BRCA2 and the subsequent abrogation of the HR pathway, leading to a radiosensitizing effect. Therefore, this study suggests that inhibition of the HR pathway may be useful to improve the therapeutic efficiency of radiotherapy for solid tumors.</p

Attenuation of conduction delay by ischemic preconditioning reduces ischemia-induced ventricular arrhythmias.

Ischemic preconditioning has been acknowledged as a powerful method of decreasing ischemic injury. However, the antiarrhythmic mechanism of ischemic preconditioning during ischemia is unclear. We studied the effects of ischemic preconditioning on arrhythmias and cardiac electrophysiology during ischemia in Langendorff rat hearts (n = 44). In the non-preconditioned group (PC(-); n = 24), the hearts underwent 5-min zero-flow global ischemia without any prior ischemic preconditioning. In the preconditioned group (PC(+); n = 20), the hearts were preconditioned by three cycles of 3-min zero-flow global ischemia and 5-min reperfusion before undergoing 5-min global ischemia. Ischemic preconditioning reduced the incidence of ischemia-induced arrhythmias (PC(-); 38.9%, PC(+): 8.3%, p < 0.05), shortened monophasic action potential duration (MAPD, P < 0.05), attenuated conduction delay (conduction time; PC(-): 234.2%, PC(+): 173.4%, P < 0.05) and increased the ventricular fibrillation threshold. Although the shortening of MAPD in PC(-) hearts was not influenced by the presence or absence of arrhythmias, conduction time prolongation at 3-min was more obvious in PC(-) hearts with arrhythmia than in PC(-) hearts without arrhythmia (PC(-) with arrhythmia: 220.2%, PC(-) without arrhythmia: 190.7%, P < 0.05). We concluded that ischemic preconditioning could protect the rat hearts from ischemia-induced arrhythmias and postulated that attenuation of conduction delay during ischemia might be an important factor in the antiarrhythmic action of ischemic preconditioning.</p

Preoperative Serum Levels of Sialyl Lewisa, Sialyl Lewisx, and Carcinoembryonic Antigens as Prognostic Factors after Resection for Primary Breast Cancer

Sialyl Lewisa (CA19-9) and sialyl LewisX antigens (CSLEXI) may play a role in tumor metastasis by serving as functional ligands in the cell adhesion system. To determine their prognostic value, we examined preoperative serum levels of CA19-9, CSLEXI, and carcinoembryonic antigen (CEA) in 64 female patients with primary breast cancer who underwent radical mastectomy. The patients were divided into two groups, termed the low- and high-antigen groups based on a value selected as a diagnostic cut-off. Correlation between the serum antigen levels, various established clinicopathologic factors, and prognosis were studied by univariate and multivariate analysis. The high- CEA group was at a more advanced stage (including T factor, N factor, M factor, and Stage) than the low-CEA group. Patients with high serum levels of CEA had shorter disease- specific intervals than those with low serum levels (P <0.0001), whereas disease-specific intervals did not differ between low- and high-CA19-9 or CSLEXI groups. A Cox\u27s regression multivariate analysis revealed a high serum CEA level as an independent factor for worse outcome, separate from Stage. In conclusion, an elevated preoperative serum CEA level was a predictor for poor outcome after radical mastectomy for breast cancer, while CA19-9 and CSLEX1 were not

Expression of monocyte chemoattractant protein-1 in idiopathic dilated cardiomyopathy

Immunological factors have been involved in the pathogenesis of dilated cardiomyopathy (DCM). The cytotoxic action of macrophages is one of the main factors causing cardiac myocyte damage. Monocyte chemoattractant protein-1 (MCP-1) is a major signal for the accumulation of monocytes/macrophages. We examined whether MCP-1 was expressed in the myocardium of DCM patients and whether the expression level was correlated with the degree of impairment of cardiac function. The expression of MCP-1 in the myocardium was determined by immunohistochemistry in endomyocardial biopsy samples from 13 patients. The expression of MCP-1 was found in all myocardial samples from DCM patients but not in those from control subjects. Positive staining for MCP-1 was distinct in cardiac myocytes, interstitium and infiltrating cells. Semi-quantitative analysis revealed that the expression of MCP-1 was inversely correlated with left ventricular ejection fraction. In conclusion, the expression level of MCP-1 in the myocardium was correlated with the degree of impairment of cardiac function in patients with DCM.</p

EMPRESS. XI. SDSS and JWST Search for Local and z~4-5 Extremely Metal-Poor Galaxies (EMPGs): Clustering and Chemical Properties of Local EMPGs

We search for local extremely metal-poor galaxies (EMPGs), selecting photometric candidates by broadband color excess and machine-learning techniques with the SDSS photometric data. After removing stellar contaminants by shallow spectroscopy with Seimei and Nayuta telescopes, we confirm that three candidates are EMPGs with 0.05--0.1 $Z_\odot$ by deep Magellan/MagE spectroscopy for faint {\sc[Oiii]}$\lambda$4363 lines. Using a statistical sample consisting of 105 spectroscopically-confirmed EMPGs taken from our study and the literature, we calculate cross-correlation function (CCF) of the EMPGs and all SDSS galaxies to quantify environments of EMPGs. Comparing another CCF of all SDSS galaxies and comparison SDSS galaxies in the same stellar mass range ($10^{7.0}-10^{8.4} M_\odot$), we find no significant ($>1\sigma$) difference between these two CCFs. We also compare mass-metallicity relations (MZRs) of the EMPGs and those of galaxies at $z\sim$ 0--4 with a steady chemical evolution model and find that the EMPG MZR is comparable with the model prediction on average. These clustering and chemical properties of EMPGs are explained by a scenario of stochastic metal-poor gas accretion on metal-rich galaxies showing metal-poor star formation. Extending the broadband color-excess technique to a high-$z$ EMPG search, we select 17 candidates of $z\sim$ 4--5 EMPGs with the deep ($\simeq30$ mag) near-infrared JWST/NIRCam images obtained by ERO and ERS programs. We find galaxy candidates with negligible {\sc[Oiii]}$\lambda\lambda$4959,5007 emission weaker than the local EMPGs and known high-$z$ galaxies, suggesting that some of these candidates may fall in 0--0.01 $Z_\odot$, which potentially break the lowest metallicity limit known to date