bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial role in ischemia–reperfusion of rat hearts exposed to high-K+cardioplegia and clonazepam: energetic and contractile consequences
Authors: Consolini A.E. , Ragone M.I. , Conforti P. , Volonté M.G. 
Published: July 2007

The role of the mitochondrial Na/Ca-exchanger (mNCX) in hearts exposed to ischemia–reperfusion (I/R) and pretreated with cardioplegia (CPG) was studied from a mechano-calorimetric approach. No-flow ischemia (ISCH) and reperfusion (REP) were developed in isolated rat hearts pretreated with 10 µmol/L clonazepam (CLZP), an inhibitor of the mNCX, and (or) a high K+– low Ca2+solution (CPG). Left ventricular end diastolic pressure (LVEDP), pressure development during beats (P), and the steady heat release (Ht) were continuously measured and muscle contents of ATP and PCr were analyzed at the end of REP. During REP, Htincreased more than P, reducing muscle economy (P/Ht) and the ATP content. CPG induced an increase in P recovery during REP (to 90% ± 10% of preISCH) with respect to nonpretreated hearts (control, C, to 64% ± 10%, p < 0.05). In contrast, CLZP reduced P recovery of CPG-hearts (50% ± 6.4%, p < 0.05) and increased LVEDP in C hearts. To evaluate effects on sarcoplasmic reticulum (SR) function, ischemic hearts were reperfused with 10 mmol/L caffeine –36 mmol/L Na (C – caff – low Na). It increased LVEDP, which afterwards slowly relaxed, whereas Htincreased (by about 6.5 mW/g). CLZP sped up the relaxation with higher ΔHt, C – caff – low Na produced higher contracture and lower Htin perfused than in ischemic hearts. Values of ΔHtwere compared with reported fluxes of Ca2+-transporters, suggesting that mitochondria may be in part responsible for the ΔHtduring C – caff – low Na REP. Results suggest that ISCH–REP reduced the SR store for the recovery of contractility, but induced Ca2+movement from the mitochondria to the SR stores. Also, mitochondria and SR are able to remove cytosolic Ca2+during overloads (as under caffeine), through the mNCX and the uniporter. CPG increases Ca2+cycling from mitochondria to the SR, which contributes to the higher recovery of P. In contrast, CLZP produces a deleterious effect on ISCH–REP associated with higher heat release and reduced resynthesis of high energy phosphates, which suggests the induction of mitochondrial Ca cycling and uncoupling.
Investigation of the vasorelaxant effects of 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1) and diethylamine/nitric oxide (DEA/NO) on the human radial artery used as coronary bypass graft
Authors: Berkan Ocal , Bagcivan Ihsan , Kaya Tijen , Yildirim Kemal , Yildirim Sahin , Doğan Kasım 
Published: July 2007

The radial artery (RA) is used as a spastic coronary bypass graft. This study was designed to investigate the mechanism of vasorelaxant effects of YC-1 (3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole), a nitric oxide (NO)-independent soluble guanylate cyclase (sGC) activator, and DEA/NO (diethylamine/nitric oxide), a NO-nucleophile adduct, on the human RA. RA segments (n = 25) were obtained from coronary artery bypass grafting patients and were divided into 3–4 mm vascular rings.Using the isolated tissue bath technique, the endothelium-independent vasodilatation function was tested in vitro by the addition of cumulative concentrations of YC-1 (10−10 to 3 × 10−7 mol/L) and DEA/NO (10−8 to 3 × 10−5 mol/L) following vasocontraction by phenylephrine in the presence or absence of 10−5 mol/L ODQ (1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one), the selective sGC inhibitor, 10−7 mol/L iberiotoxin, a blocker of Ca2+-activated K+ channels, or 10−5 mol/L ODQ plus 10−7 mol/L iberiotoxin. We also evaluated the effect of YC-1 and DEA/NO on the cGMP levels in vascular rings obtained from human radial artery (n = 6 for each drug). YC-1 (10−10 to 3 × 10−7 mol/L) and DEA/NO (10−8 to 3 × 10−5 mol/L) caused the concentration-dependent vasorelaxation in RA rings precontracted with phenylephrine (10−5 mol/L) (n = 20 for each drug). Pre-incubation of RA rings with ODQ, iberiotoxin, or ODQ plus iberiotoxin significantly inhibited the vasorelaxant effect of YC-1, but the inhibitor effect of ODQ plus iberiotoxin was significantly more than that of ODQ and iberiotoxin alone (p < 0.05). The vasorelaxant effect of DEA/NO almost completely abolished in the presence of ODQ and iberiotoxin plus ODQ, but did not significantly change in the presence of iberiotoxin alone (p > 0.05). The pEC50 value of DEA/NO was significantly lower than those for YC-1 (p < 0.01), with no change Emax values in RA rings. In addition, YC-1-stimulated RA rings showed more elevation in cGMP than that of DEA/NO (p < 0.05). These findings indicate that YC-1 is a more potent relaxant than DEA/NO in the human RA. The relaxant effects of YC-1 could be due to the stimulation of the sGC and Ca2+-sensitive K+channels, whereas the relaxant effects of DEA/NO could be completely due to the stimulation of the sGC. YC-1 and DEA/NO may be effective as vasodilator for the short-term treatment of perioperative spasm of coronary bypass grafts.
The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts
Authors: Onay-Besikci Arzu , Guner Sahika , Arioglu Ebru , Ozakca Isil , Ozcelikay A. Tanju , Altan V. Melih 
Published: July 2007

Clinical and experimental evidence suggest that increased rates of fatty acid oxidation in the myocardium result in impaired contractile function in both normal and diabetic hearts. Glucose utilization is decreased in type 1 diabetes, and fatty acid oxidation dominates for energy production at the expense of an increase in oxygen requirement. The objective of this study was to examine the effect of chronic treatment with trimetazidine (TMZ) on cardiac mechanical function and fatty acid oxidation in streptozocin (STZ)-diabetic rats. Spontaneously beating hearts from male Sprague–Dawley rats were subjected to a 60-minute aerobic perfusion period with a recirculating Krebs–Henseleit solution containing 11 mmol/L glucose, 100 μU/mL insulin, and 0.8 mmol/L palmitate prebound to 3% bovine serum albumin (BSA). Mechanical function of the hearts, as cardiac output × heart rate (in (mL/min)·(beats/min)·10–2), was deteriorated in diabetic (73 ± 4) and TMZ-treated diabetic (61 ± 7) groups compared with control (119 ± 3) and TMZ-treated controls (131 ± 6). TMZ treatment increased coronary flow in TMZ-treated control (23 ± 1 mL/min) hearts compared with untreated controls (18 ± 1 mL/min). The mRNA expression of 3-ketoacyl-CoA thiolase (3-KAT) was increased in diabetic hearts. The inhibitory effect of TMZ on fatty acid oxidation was not detected at 0.8 mmol/L palmitate in the perfusate. Addition of 1 μmol/L TMZ 30 min into the perfusion did not affect fatty acid oxidation rates, cardiac work, or coronary flow. Our results suggest that higher expression of 3-KAT in diabetic rats might require increased concentrations of TMZ for the inhibitory effect on fatty acid oxidation. A detailed kinetic analysis of 3-KAT using different concentrations of fatty acid will determine the fatty acid inhibitory concentration of TMZ in diabetic state where plasma fatty acid levels are increased.
Dexamethasone-induced insulin resistance is associated with increased connexin 36 mRNA and protein expression in pancreatic rat islets
Authors: Rafacho A. , Roma L.P. , Taboga S.R. , Boschero A.C. , Bosqueiro J.R. 
Published: July 2007

Augmented glucose-stimulated insulin secretion (GSIS) is an adaptive mechanism exhibited by pancreatic islets from insulin-resistant animal models. Gap junction proteins have been proposed to contribute to islet function. As such, we investigated the expression of connexin 36 (Cx36), connexin 43 (Cx43), and the glucose transporter Glut2 at mRNA and protein levels in pancreatic islets of dexamethasone (DEX)-induced insulin-resistant rats. Study rats received daily injections of DEX (1 mg/kg body mass, i.p.) for 5 days, whereas control rats (CTL) received saline solution. DEX rats exhibited peripheral insulin resistance, as indicated by the significant postabsorptive insulin levels and by the constant rate for glucose disappearance (KITT). GSIS was significantly higher in DEX islets (1.8-fold in 16.7 mmol/L glucose vs. CTL, p < 0.05). A significant increase of 2.25-fold in islet area was observed in DEX vs. CTL islets (p < 0.05). Cx36 mRNA expression was significantly augmented, Cx43 diminished, and Glut2 mRNA was unaltered in islets of DEX vs. CTL (p < 0.05). Cx36 protein expression was 1.6-fold higher than that of CTL islets (p < 0.05). Glut2 protein expression was unaltered and Cx43 was not detected at the protein level. We conclude that DEX-induced insulin resistance is accompanied by increased GSIS and this may be associated with increase of Cx36 protein expression.
PARTICLE MESH HYDRODYNAMICS FOR ASTROPHYSICS SIMULATIONS
Authors: CHATELAIN PHILIPPE , COTTET GEORGES-HENRI , KOUMOUTSAKOS PETROS 
Published: July 2007

We present a particle method for the simulation of three dimensional compressible hydrodynamics based on a hybrid Particle-Mesh discretization of the governing equations. The method is rooted on the regularization of particle locations as in remeshed Smoothed Particle Hydrodynamics (rSPH). The rSPH method was recently introduced to remedy problems associated with the distortion of computational elements in SPH, by periodically re-initializing the particle positions and by using high order interpolation kernels. In the PMH formulation, the particles solely handle the convective part of the compressible Euler equations. The particle quantities are then interpolated onto a mesh, where the pressure terms are computed. PMH, like SPH, is free of the convection CFL condition while at the same time it is more efficient as derivatives are computed on a mesh rather than particle-particle interactions. PMH does not detract from the adaptive character of SPH and allows for control of its accuracy. We present simulations of a benchmark astrophysics problem demonstrating the capabilities of this approach.
Insulin-like Growth Factor Receptor as a Therapeutic Target in Head and Neck Cancer
Authors: Barnes Christopher J. , Ohshiro Kazufumi , Rayala Suresh K. , El-Naggar Adel K. , Kumar Rakesh 
Published: July 2007

Abstract
Purpose: Insulin-like growth factor type I receptor (IGF-IR) plays critical roles in epithelial cancer cell development, proliferation, motility, and survival, and new therapeutic agents targeting IGF-IR are in development. Another receptor tyrosine kinase, the epidermal growth factor receptor (EGFR), is an established therapeutic target in head and neck cancer and IGF-IR/EGFR heterodimerization has been reported in other epithelial cancers. The present study was undertaken to determine the effects of anti–IGF-IR therapeutic targeting on cell signaling and cancer cell phenotypes in squamous cell carcinomas of the head and neck (SCCHN).
Experimental Design: The therapeutic efficacy of the human anti–IGF-IR antibody IMC-A12 alone and in combination with the EGFR blocking antibody cetuximab (C225) was tested in SCCHN cell lines and in tumor xenografts.
Results: IGF-IR was overexpressed in human head and neck cancer cell lines and tumors. Pretreatment of serum-starved 183A or TU159 SCCHN cell lines with A12 (10 μg/mL) blocked IGF-stimulated activation of IGF-IR, insulin receptor substrate (IRS)-1 and IRS-2, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase. A12 induced G0-G1 cell cycle arrest and blocked cell growth, motility, and anchorage-independent growth. Stimulation of head and neck cancer cells with either IGF or EGF resulted in IGF-IR and EGFR heterodimerization, but only IGF caused activating phosphorylation of both receptors. Combined treatment with A12 and the EGFR blocking antibody C225 was more effective at reducing cell proliferation and migration than either agent alone. Finally, TU159 tongue cancer cell xenografts grown in athymic nude mice were treated thrice weekly for 4 weeks with vehicle, A12 (40 mg/kg i.p.), C225 (40 mg/kg i.p.), or both agents (n = 8 mice per group; 2 tumors per mouse). Linear regression slope analysis showed significant differences in median tumor volume over time between all three treatment groups and the control group. Complete regression was seen in 31% (A12), 31% (C225), and 44% (A12 + C225) of tumors.
Conclusion: Here we found the overexpression of IGF-IR, the functional heterodimerization of IGF-IR and EGFR, and effective therapeutic targeting of these receptors in human head and neck cancer xenografts.
Tamoxifen Induces Heparanase Expression in Estrogen Receptor–Positive Breast Cancer
Authors: Cohen Irit , Maly Bella , Simon Itamar , Meirovitz Amichay , Pikarsky Eli , Zcharia Eyal , Peretz Tamar , Vlodavsky Israel , Elkin Michael 
Published: July 2007

AbstractPurpose: Mammalian heparanase degrades heparan sulfate, the main polysaccharide of the basement membrane. Heparanase is an important determinant in cancer progression, acting via the breakdown of extracellular barriers for invasion, as well as release of heparan sulfate–bound angiogenic and growth-promoting factors. The present study was undertaken to elucidate molecular mechanisms responsible for heparanase overexpression in breast cancer.Experimental Design: To characterize heparanase regulation by estrogen and tamoxifen and its clinical relevance for breast tumorigenesis, we applied immunohistochemical analysis of tissue microarray combined with chromatin immunoprecipitation assay, reverse transcription-PCR, and Western blot analysis.Results: A highly significant correlation (P &lt; 0.0001) between estrogen receptor (ER) positivity and heparanase overexpression was found in breast cancer. Binding of ER to heparanase promoter accompanied estrogen-induced increase in heparanase expression by breast carcinoma cells. Surprisingly, heparanase transcription was also stimulated by tamoxifen, conferring a proliferation advantage to breast carcinoma cells grown on a naturally produced extracellular matrix. Heparanase overexpression was invariably detected in ER-positive second primary breast tumors, developed in patients receiving tamoxifen for the initial breast carcinoma. The molecular mechanism of the estrogenlike effect of tamoxifen on heparanase expression involves recruitment of transcription coactivator AIB1 to the heparanase promoter.Conclusions: Heparanase induction by ligand-bound ER represents an important pathway in breast tumorigenesis and may be responsible, at least in part, for the failure of tamoxifen therapy in some patients. Our study provides new insights on breast cancer progression and endocrine therapy resistance, offering future strategies for delaying or reversing this process.
RAD001 Inhibits Human Ovarian Cancer Cell Proliferation, Enhances Cisplatin-Induced Apoptosis, and Prolongs Survival in an Ovarian Cancer Model
Authors: Mabuchi Seiji , Altomare Deborah A. , Cheung Mitchell , Zhang Lili , Poulikakos Poulikos I. , Hensley Harvey H. , Schilder Russell J. , Ozols Robert F. , Testa Joseph R. 
Published: July 2007

Abstract
Purpose: mTOR (mammalian target of rapamycin) plays a central role in regulating cell growth and cell cycle progression and is regarded as a promising therapeutic target. We examined whether mTOR inhibition by RAD001 (everolimus) is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with cisplatin.
Experimental Design: Using four human ovarian cancer cell lines, we determined the effect of RAD001 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Western blot, and apoptosis assays. We evaluated the association between phospho-AKT/mTOR activity and RAD001 sensitivity. We also determined the effect of RAD001 on tumor growth and malignancy using mice inoculated with human ovarian cancer cells.
Results: RAD001 markedly inhibited cell proliferation of human ovarian carcinoma cells with high AKT activity (OVCAR10 and SKOV-3), but the effect was minimal in cells with low AKT activity (OVCAR4 and OVCAR5). Sensitivity to RAD001 was independent of p53 expression. RAD001 inhibited the phosphorylation of downstream 4E-BP1 and p70S6 kinase and attenuated the expression of Myc. RAD001 also attenuated the expression of HIF-1α and vascular endothelial growth factor, important factors in angiogenesis and tumor invasiveness. RAD001 enhanced cisplatin-induced apoptosis in cells with high AKT/mTOR activity, with minimal effect in cells with low AKT-mTOR activity. Mouse xenografts of SKOV-3 cells revealed that RAD001 inhibits tumor growth, angiogenesis, and i.p. dissemination and ascites production and prolongs survival. Moreover, treatment with RAD001 significantly enhanced the therapeutic efficacy of cisplatin in vivo.
Conclusion: These results indicate that RAD001 could have therapeutic efficacy in human ovarian cancers with hyperactivated AKT/mTOR signaling.
Regulation of p53 Expression in Response to 5-Fluorouracil in Human Cancer RKO Cells
Authors: Ju Jingfang , Schmitz John C. , Song Bo , Kudo Kenji , Chu Edward 
Published: July 2007

Abstract
Purpose: The purpose of the study is to investigate the regulation of p53 expression in response to 5-fluorouracil (5-FU) in human colon cancer cells.
Experimental Design: Human colon cancer RKO cells were used as our model system. The levels of p53 expression and p53 protein stability in response to 5-FU and doxorubicin were investigated. In addition, the acetylation and phosphorylation status of p53 after 5-FU and doxorubicin treatment was analyzed by Western immunoblot analysis.
Results: Treatment of human colon cancer RKO cells with 10 μmol/L 5-FU resulted in significantly increased levels of p53 protein with maximal induction observed at 24 h. The level of acetylated p53 after 5-FU exposure remained unchanged, whereas the phosphorylated form of p53 was expressed only after 24 h drug treatment. Northern blot analysis revealed no change in p53 mRNA levels after 5-FU treatment. No differences were observed in the half-life of p53 protein in control and 5-FU–treated cells, suggesting that the increase in p53 was the direct result of newly synthesized protein. In contrast, the maximal induction of p53, in response to doxorubicin, occurred at an earlier time point (4 h) when compared with cells treated with 5-FU (24 h). No corresponding change in p53 mRNA was observed. Levels of both the acetylated and phosphorylated forms of p53 were markedly increased upon doxorubicin exposure when compared with treatment with 5-FU, resulting in a significantly prolonged half-life of p53 (120 versus 20 min).
Conclusion: These results, taken together, suggest that the regulatory mechanisms controlling p53 expression, in response to a cellular stress, are complex and are dependent upon the specific genotoxic agent. With regard to 5-FU, we show that translational regulation is an important process for controlling p53 expression. Studies are under way to define the specific mechanism(s) that control 5-FU–mediated translational regulation of p53.
Association of Cysteine-Rich Secretory Protein 3 and β-Microseminoprotein with Outcome after Radical Prostatectomy
Authors: Bjartell Anders S. , Al-Ahmadie Hikmat , Serio Angel M. , Eastham James A. , Eggener Scott E. , Fine Samson W. , Udby Lene , Gerald William L. , Vickers Andrew J. , Lilja Hans , Reuter Victor E. , Scardino Peter T. 
Published: July 2007

AbstractPurpose: It has been suggested that cysteine-rich secretory protein 3 (CRISP-3) and β-microseminoprotein (MSP) are associated with outcome in prostate cancer. We investigated whether these markers are related to biochemical recurrence and whether addition of the markers improves prediction of recurring disease.Experimental Design: Tissue microarrays of radical prostatectomy specimens were analyzed for CRISP-3 and MSP by immunohistochemistry. Associations between marker positivity and postprostatectomy biochemical recurrence [prostate-specific antigen (PSA) &gt;0.2 ng/mL with a confirmatory level] were evaluated by univariate and multivariable Cox proportional hazards regression. Multivariable analyses controlled for preoperative PSA and pathologic stage and grade.Results: Among 945 patients, 224 had recurrence. Median follow-up for survivors was 6.0 years. Patients positive for CRISP-3 had smaller recurrence-free probabilities, whereas MSP-positive patients had larger recurrence-free probabilities. On univariate analysis, the hazard ratio for patients positive versus negative for CRISP-3 was 1.53 (P = 0.010) and for MSP was 0.63 (P = 0.004). On multivariable analysis, both CRISP-3 (P = 0.007) and MSP (P = 0.002) were associated with recurrence. The hazard ratio among CRISP-3–positive/MSP-negative patients compared with CRISP-3–negative/MSP-positive patients was 2.38. Adding CRISP-3 to a base model that included PSA and pathologic stage and grade did not enhance the prediction of recurrence, but adding MSP increased the concordance index minimally from 0.778 to 0.781.Conclusion: We report evidence that CRISP-3 and MSP are independent predictors of recurrence after radical prostatectomy for localized prostate cancer. However, addition of the markers does not importantly improve the performance of existing predictive models. Further research should aim to elucidate the functions of CRISP-3 and MSP in prostate cancer cells.
The Effect of Repeated Administration of Cyclophosphamide on Cytochrome P450 2B in Rats
Authors: Afsharian Parvaneh , Terelius Ylva , Hassan Zuzana , Nilsson Christina , Lundgren Stefan , Hassan Moustapha 
Published: July 2007

AbstractPurpose: The prodrug cyclophosphamide (CPA) is activated by cytochrome P450 (CYP) enzymes. CPA is one of the corner stones in all cancer treatment. We have studied the effect of repeated doses of CPA given at different time intervals on the mRNA, protein levels, and enzyme activity of CYPs in rats.Experimental Design: Two groups of animals (A-75 and A-150) were treated with four doses of CPA (75 and 150 mg/kg, respectively) at short time intervals (6 h). The third group of animals (B-150) was treated with 150 mg/kg at 24-h intervals. Three animals were killed 30 min after administration, and three animals immediately before the next dose.Results: CYP2B1 and CYP2B2 mRNAs were significantly induced at 6 h after each dose in group A-75 (maximum of 2100-fold and 60-fold after the third dose, respectively), whereas the mRNA levels measured at 6 h postadministration in group A-150 were 1,490-fold and 36-fold after the second dose. In group B-150, no significant induction of mRNA levels was observed. CYP2B1 and CYP2B2 protein levels also increased with increased mRNAs. Plasma levels of 4-hydroxy-CPA measured at 30 min after dose correlated well with the increase in protein levels.Conclusion: Up-regulation of CYP2B mRNA, with a concomitant increase in protein expression and activity, were observed after repeated administration of low doses of CPA compared with that found using higher doses, possibly due to toxicity counteracting induction. These results may help in designing more effective dosing schedules for CPA.