bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern
Authors: Berglund P , Stighall M , Jirström K , Rydén L , Fernö M , Nordenskjöld B , Landberg G
Published: May 2007

Aims:

To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours.

Methods:

Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections.

Results:

Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels.

Conclusion:

The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.
RECENT ADVANCES IN PULSED LASER ABLATED PLASMA PLUMES: A REVIEW
Authors: DWIVEDI ASHUTOSH
Published: May 2007

Pulsed laser ablation is a process in which an intense laser pulse interacts with the matter producing plasma. The present work describes the theoretical work being conducted in the past for the pulsed laser ablation phenomenon. It incorporates the theoretical models being proposed by various researchers around the globe for pulsed laser ablation. The main processes involved in the laser–matter interaction leading to plasma plume formation are the absorption and the reflection of the incident laser light by the condensed phase, ablation of the condensed phase, absorption of the laser light within the expanding plume, expansion of the vapor-plasma plume, and in the case of pulsed laser desorption, the interaction of the ablated species with the substrate surface. Thus the plasma, produced in the laser–matter interaction, plays an important role in the pulsed laser ablation (PLA) process.
DEPOSITION AND CHARACTERIZATION OF TiN-COATED STEELS AT VARIOUS N2 GAS FLOW RATES WITH CONSTANT ETCHING BY USING CAPVD TECHNIQUE
Authors: ALI MUBARAK , HAMZAH ESAH BINTI , TOFF MOHD RADZI HJ. MOHD
Published: May 2007

Cathodic Arc Physical Vapor Deposition (CAPVD), a technique used for the deposition of hard coatings, for tooling applications, has many advantages. The main drawback of this technique is the formation of macrodroplets (MDs) during deposition, resulting in films with rougher morphology. Constant etching, by increasing nitrogen gas flow rate up to 200 sccm, helped in reducing the MD size and number; at higher rates, of say 300 sccm, the behavior was reversed. Minimum value of surface roughness recorded at 200 sccm was measured via both surface roughness tester and atomic force microscopy (AFM). Micro-Vickers hardness of TiN -coated tool showed about 564% times increase in hardness than the uncoated one. Scratch tester was used to study the critical loads for the coating and the excellent adhesion achievable, of say 200 sccm, was demonstrated, with relevance to the various modes.
Prolactin-stimulated transepithelial calcium transport in duodenum and Caco-2 monolayer are mediated by the phosphoinositide 3-kinase pathway
Authors: Jantarajit Walailuk , Thongon Narongrit , Pandaranandaka Jantarima , Teerapornpuntakit Jarinthorn , Krishnamra Nateetip , Charoenphandhu Narattaphol
Published: May 2007

Prolactin (PRL) has been shown to stimulate intestinal calcium absorption but the mechanism was still unknown. This study aimed to investigate the mechanism and signaling pathway by which PRL enhanced calcium transport in the rat duodenum and Caco-2 monolayer. Both epithelia strongly expressed mRNAs and proteins of PRL receptors. Ussing chamber technique showed that the duodenal active calcium fluxes were increased by PRL in a dose-response manner with the maximal effective dose of 800 ng/ml. This response diminished after exposure to LY-294002, a phosphoinositide 3-kinase (PI3K) inhibitor. Caco-2 monolayer gave similar response to PRL with the maximal effective dose of 600 ng/ml. By nullifying the transepithelial potential difference, we showed that the voltage-dependent paracellular calcium transport did not contribute to the PRL-enhanced flux in Caco-2 monolayer. In contrast, the calcium gradient-dependent paracellular transport and calcium permeability were increased by PRL. Effects of PRL on Caco-2 monolayer were abolished by PI3K inhibitors (LY-294002 and wortmannin), but not by inhibitors of MEK (U-0126) or JAK2 (AG-490). To investigate whether the PRL-enhanced paracellular transport was linked to changes in the epithelial charge selectivity, the permeability ratio of sodium and chloride ( PNa/ PCl) was determined. We found that PRL elevated the PNa/ PClin both epithelia, and the effects were blocked by PI3K inhibitors. In conclusion, PRL directly and rapidly stimulated the active and passive calcium transport in the rat duodenum and Caco-2 monolayer via the nongenomic PI3K-signaling pathway. This PRL-enhanced paracellular calcium transport could have resulted from altered charge selectivity.
Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective
Authors: Quintanilla María Elena , Tampier Lutske , Sapag Amalia , Gerdtzen Ziomara , Israel Yedy
Published: May 2007

Individuals who carry the most active alcohol dehydrogenase (ADH) isoforms are protected against alcoholism. This work addresses the mechanism by which a high ADH activity leads to low ethanol intake in animals. Male and female ethanol drinker rats (UChB) were allowed access to 10% ethanol for 1 h. Females showed 70% higher hepatic ADH activity and displayed 60% lower voluntary ethanol intake than males. Following ethanol administration (1 g/kg ip), females generated a transient blood acetaldehyde increase (“burst”) with levels that were 2.5-fold greater than in males ( P < 0.02). Castration of males led to 1) an increased ADH activity (+50%, P < 0.001), 2) the appearance of an acetaldehyde burst (3- to 4-fold vs. sham), and 3) a reduction of voluntary ethanol intake comparable with that of naïve females. The ADH inhibitor 4-methylpyrazole blocked the appearance of arterial acetaldehyde and increased ethanol intake. Since the release of NADH from the ADH·NADH complex constitutes the rate-limiting step of ADH (but not of ALDH2) activity, endogenous NADH oxidizing substrates present at the time of ethanol intake may contribute to the acetaldehyde burst. Sodium pyruvate given at the time of ethanol administration led to an abrupt acetaldehyde burst and a greatly reduced voluntary ethanol intake. Overall, a transient surge of arterial acetaldehyde occurs upon ethanol administration due to 1) high ADH levels and 2) available metabolites that can oxidize hepatic NADH. The acetaldehyde burst is strongly associated with a marked reduction in ethanol intake.
Caffeine-activated large-conductance plasma membrane cation channels in cardiac myocytes: characteristics and significance
Authors: Zhang Yu-an , Tuft Richard A. , Lifshitz Lawrence M. , Fogarty Kevin E. , Singer Joshua J. , Zou Hui
Published: May 2007

Caffeine-activated, large-conductance, nonselective cation channels (LCCs) have been found in the plasma membrane of isolated cardiac myocytes in several species. However, little is known about the effects of opening these channels. To examine such effects and to further understand the caffeine-activation mechanism, we carried out studies using whole-cell patch-clamp techniques with freshly isolated cardiac myocytes from rats and mice. Unlike previous studies, thapsigargin was used so that both the effect of opening LCCs and the action of caffeine were independent of Ca2+release from intracellular stores. These Ca2+-permeable LCCs were found in a majority of the cells from atria and ventricles, with a conductance of ∼370 pS in rat atria. Caffeine and all its direct metabolic products (theophylline, theobromine, and paraxanthine) activated the channel, while isocaffeine did not. Although they share some similarities with ryanodine receptors (RyRs, the openings of which give rise to Ca2+sparks), LCCs also showed some different characteristics. With simultaneous Ca2+imaging and current recording, the localized fluorescence increase due to Ca2+entry through a single opening of an LCC (SCCaFT) was detected. When membrane potential, instead of current, was recorded, SCCaFT-like fluorescence transients (indicating single LCC openings) were found to accompany membrane depolarizations. To our knowledge, this is the first report directly linking membrane potential changes to a single opening of an ion channel. Moreover, these events in cardiac cells suggest a possible additional mechanism by which caffeine and theophylline contribute to the generation of cardiac arrhythmias.
Increase in pulse wavelength causes the systemic arterial tree to degenerate into a classical windkessel
Authors: Mohiuddin Mohammad W. , Laine Glen A. , Quick Christopher M.
Published: May 2007

Two competing schools of thought ascribe vascular disease states such as isolated systolic hypertension to fundamentally different arterial system properties. The “windkessel school” describes the arterial system as a compliant chamber that distends and stores blood and relates pulse pressure to total peripheral resistance ( Rtot) and total arterial compliance ( Ctot). Inherent in this description is the assumption that arterial pulse wavelengths are infinite. The “transmission school,” assuming a finite pulse wavelength, describes the arterial system as a network of vessels that transmits pulses and relates pulse pressure to the magnitude, timing, and sites of pulse-wave reflection. We hypothesized that the systemic arterial system, described by the transmission school, degenerates into a windkessel when pulse wavelengths increase sufficiently. Parameters affecting pulse wavelength (i.e., heart rate, arterial compliances, and radii) were systematically altered in a realistic, large-scale, human arterial system model, and the resulting pressures were compared with those assuming a classical (2-element) windkessel with the same Rtot and Ctot. Increasing pulse wavelength as little as 50% (by changing heart rate −33.3%, compliances −55.5%, or radii +50%) caused the distributed arterial system model to degenerate into a classical windkessel ( r2 = 0.99). Model results were validated with analysis of representative human aortic pressure and flow waveforms. Because reported changes in arterial properties with age can markedly increase pulse wavelength, results suggest that isolated systolic hypertension is a manifestation of an arterial system that has degenerated into a windkessel, and thus arterial pressure is a function only of aortic flow, Rtot, and Ctot.
Differential and combined effects of cardiotrophin-1 and TGF-β1on cardiac myofibroblast proliferation and contraction
Authors: Drobic Vanja , Cunnington Ryan H. , Bedosky Kristen M. , Raizman Joshua E. , Elimban Vinit V. , Rattan Sunil G. , Dixon Ian M. C.
Published: May 2007

Myofibroblasts respond to an array of signals from mitogens and cytokines during the course of wound healing following a myocardial infarction (MI), and these signals may coordinate ventricular myofibroblast proliferation. Furthermore, myofibroblasts are contractile and contribute to wound contraction by imparting mechanical tension on surrounding extracellular matrix. Although TGF-β1, CT-1, and PDGF-BB participate in various stages of post-MI wound healing, their combined net effect(s) on myofibroblast function is unknown. We investigated myofibroblast proliferation, expression of cell cycle proteins, and contractile function of cells treated with TGF-β1and/or CT-1. We confirmed that TGF-β1(10 ng/ml) suppresses proliferation of these cells, whereas CT-1 (10 ng/ml) and, for comparative purposes, PDGF-BB (1 ng/ml) treatments were associated with proliferation. Specific TGF-β1treatment ablated CT-1-induced myofibroblast proliferation. TGF-β1effects were specific, as they were suppressed by either TGF-β-neutralizing antibody or viral Smad7 overexpression. TGF-β1treatment also increased expression of p27 and decreased expression of cyclin E and Cdk2 in primary cells. CT-1 (10 ng/ml) treatment of myofibroblasts had no effect on collagen gel deformation versus controls, whereas TGF-β1(10 ng/ml) and PDGF (10 ng/ml) treatments were associated with significant cell contraction; again, TGF-β1-mediated contraction was unaffected by CT-1. Alone, CT-1 and TGF-β1treatments exert opposing effects on myofibroblast function, whereas in combination TGF-β1-mediated effects supersede those of CT-1 (and PDGF-BB). Thus TGF-β1and CT-1 exert differential effects on myofibroblast proliferation and contraction in vitro, and we suggest that a balance of these effects may be important for the execution of normal cardiac wound healing.
Small-molecule cyclic αVβ3 antagonists inhibit sickle red cell adhesion to vascular endothelium and vasoocclusion
Authors: Finnegan Eileen M. , Barabino Gilda A. , Liu Xiao-du , Chang Hee-Yoon , Jonczyk Alfred , Kaul Dhananjay K.
Published: May 2007

Abnormal adhesion of sickle red blood cells (SS RBCs) to vascular endothelium may play an important role in vasoocclusion in sickle cell disease. Accruing evidence shows that endothelial αVβ3-integrin has an important role in SS RBC adhesion because of its ability to bind several adhesive proteins implicated in this interaction. In the present studies, we tested therapeutic efficacy of small-molecule cyclic pentapeptides for their ability to block αVβ3-mediated SS RBC adhesion by using two well-established assay systems, i.e., cultured human umbilical vein endothelial cells (HUVEC) and artificially perfused mesocecum vasculature of the rat under flow conditions. We tested the efficacy of two RGD-containing cyclic pentapeptides, i.e., cRGDFV (EMD 66203) and cRGDF-ACHA (α-amino cyclohexyl carboxylic acid) (EMD 270179), based on their known ability to bind αVβ3. An inactive peptide, EMD 135981 (cRβ-ADFV) was used as control. Cyclization and the introduction of d-Phe (F) results in a marked increase in the ability of cyclic peptides to selectively bind αVβ3 receptors. In the mesocecum vasculature, both EMD 66203 and EMD 270179 ameliorated platelet-activating factor-induced enhanced SS RBC adhesion, postcapillary blockage, and significantly improved hemodynamic behavior. Infusion of a fluorescent derivative of EMD 66203 resulted in colocalization of the antagonist with vascular endothelium. Also, pretreatment of HUVEC with either αVβ3 antagonist resulted in a significant decrease in SS RBC adhesion. Because of their metabolic stability, the use of these cyclic αVβ3 antagonists may constitute a novel therapeutic strategy to block SS RBC adhesion and associated vasoocclusion under flow conditions.
Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress
Authors: Townsend Paul A. , Davidson Sean M. , Clarke Samantha J. , Khaliulin Igor , Carroll Christopher J. , Scarabelli Tiziano M. , Knight Richard A. , Stephanou Anastasis , Latchman David S. , Halestrap Andrew P.
Published: May 2007

Urocortin (UCN) protects hearts against ischemia and reperfusion injury whether given before ischemia or at reperfusion. Here we investigate the roles of PKC, reactive oxygen species, and the mitochondrial permeability transition pore (MPTP) in mediating these effects. In Langendorff-perfused rat hearts, acute UCN treatment improved hemodynamic recovery during reperfusion after 30 min of global ischemia; this was accompanied by less necrosis (lactate dehydrogenase release) and MPTP opening (mitochondrial entrapment of 2-[3H]deoxyglucose). UCN pretreatment protected mitochondria against calcium-induced MPTP opening, but only if the mitochondria had been isolated from hearts after reperfusion. These mitochondria also exhibited less protein carbonylation, suggesting that UCN decreases levels of oxidative stress. In isolated adult and neonatal rat cardiac myocytes, both acute (60 min) and chronic (16 h) treatment with UCN reduced cell death following simulated ischemia and re-oxygenation. This was accompanied by less MPTP opening as measured using tetramethylrhodamine methyl ester. The level of oxidative stress during reperfusion was reduced in cells that had been pretreated with UCN, suggesting that this is the mechanism by which UCN desensitizes the MPTP to reperfusion injury. Despite the fact that we could find no evidence that either PKC-ε or PKC-α translocate to the mitochondria following acute UCN treatment, inhibition of PKC with chelerythrine eliminated the effect of UCN on oxidative stress. Our data suggest that acute UCN treatment protects the heart by inhibiting MPTP opening. However, the mechanism appears to be indirect, involving a PKC-mediated reduction in oxidative stress.
Impairments in microvascular reactivity are related to organ failure in human sepsis
Authors: Doerschug Kevin C. , Delsing Angela S. , Schmidt Gregory A. , Haynes William G.
Published: May 2007

Severe sepsis is a systemic inflammatory response to infection resulting in acute organ dysfunction. Vascular perfusion abnormalities are implicated in the pathology of organ failure, but studies of microvascular function in human sepsis are limited. We hypothesized that impaired microvascular responses to reactive hyperemia lead to impaired oxygen delivery relative to the needs of tissue and that these impairments would be associated with organ failure in sepsis. We studied 24 severe sepsis subjects 24 h after recognition of organ dysfunction; 15 healthy subjects served as controls. Near-infrared spectroscopy (NIRS) was used to measure tissue 1) microvascular hemoglobin signal strength and 2) oxygen saturation of microvascular hemoglobin (StO2). Both values were measured in thenar skeletal muscle before and after 5 min of forearm stagnant ischemia. At baseline, skeletal muscle microvascular hemoglobin was lower in septic than control subjects. Microvascular hemoglobin increased during reactive hyperemia in both groups, but less so in sepsis. StO2 at baseline and throughout ischemia was similar between the two groups; however, the rate of tissue oxygen consumption was significantly slower in septic subjects than in controls. The rate of increase in StO2 during reactive hyperemia was significantly slower in septic subjects than in controls; this impairment was accentuated in those with more organ failure. We conclude that organ dysfunction in severe sepsis is associated with dysregulation of microvascular oxygen balance. NIRS measurements of skeletal muscle microvascular perfusion and reactivity may provide important information about sepsis and serve as endpoints in future therapeutic interventions aimed at improving the microcirculation.
Fluorescence correlation spectroscopy can probe albumin dynamics inside lung endothelial glycocalyx
Authors: Stevens Andrew P. , Hlady Vladimir , Dull Randal O.
Published: May 2007

The endothelial glycocalyx is believed to play a major role in capillary permeability by functioning as a macromolecular barrier overlying the intercellular junction. Little is known about the functional attributes of the glycocalyx (i.e., porosity and permeability) or which constituents contribute to its overall structure-function relationship. In this report, we demonstrate the utility of fluorescence correlation spectroscopy (FCS) to measure albumin diffusion rates and concentration profiles above the cell surface and overlying the intercellular junctions of lung capillary endothelial cells. Albumin diffusion rates and concentration profiles were obtained before and after enzymatic digestion of the glycocalyx with pronase, heparanase, or hyaluronidase. The results suggest a structure interacting with albumin located from 1.0 to 2.0 μm above the cell membrane capable of reducing albumin diffusion by 30% while simultaneously increasing albumin concentration fivefold. Digestion of the glycocalyx with pronase or heparanase resulted in only modest changes in albumin diffusion and concentration profiles. Hyaluronidase digestion completely eliminated albumin-glycocalyx interactions. These data also suggest that hyaluronan is a major determinant for albumin interactions with the lung endothelial glycocalyx. Confocal images of heparan sulfate and hyaluronan confirm a cell-surface layer 2–3 μm in thickness, thus supporting FCS measurements. In summary, we report the first use of FCS to probe extracellular structures and further our understanding of the structure-function relationship of the lung microvascular endothelial glycocalyx.
Modulation of airway responses by prostaglandins in young and fully grown rabbits
Authors: Larsen Gary L. , Loader Joan , Fratelli Cori , Kang June-ku Brian , Dakhama Azzeddine , Colasurdo Giuseppe N.
Published: May 2007

Maturational changes have been noted in neurally mediated contractile and relaxant responses in airways from New Zealand White rabbits. In this study, we focused on prostaglandins with bronchoprotective properties as potential modulators of airway tone in maturing rabbits. Tracheal rings from 1-, 2-, and 13-wk-old rabbits were assessed for neurally mediated contractile and relaxant responses produced by electrical field stimulation (EFS) of nerves in the presence and absence of the prostaglandin inhibitor, indomethacin (Indo). We also measured EFS-induced release of prostaglandin E2 (PGE2) and the stable metabolite of prostacyclin, 6-keto-prostaglandin F1α (6-keto-PGF1α). In the presence of Indo, EFS produced significant increases in contractile responses in segments from 1- and 2-wk-old animals but not in segments from 13-wk adult rabbits. Tracheal rings from 1- and 2-wk-old animals precontracted with neurokinin A (NKA) relaxed 100% in response to EFS when Indo was not in the bath. In rings from 13-wk-old animals, relaxation was 40%. With Indo, relaxation was abolished in 1-wk-old animals and reduced to 30% in the 2- and 13-wk-old groups. Buffer from baths collected after EFS had significant increases in PGE2 and 6-keto-PGF1α released from tissues from 1- vs. 2- and 13-wk-old animals. Dose response curves to PGE2 using tissues precontracted to NKA showed significant increases in relaxant responses in 1- and 2- vs. 13-wk-old rabbits. In rabbit airways, this study demonstrates enhanced modulation of airway tone by PGE2 and greater release of the bronchoprotective prostaglandins PGE2 and prostacyclin early in life.
Transcriptional profiling ofOvis ariesidentifiesOvar-DQA1allele frequency differences between nematode-resistant and susceptible selection lines
Authors: Keane Orla M. , Dodds Ken G. , Crawford Allan M. , McEwan John C.
Published: May 2007

Gastrointestinal nematodes are a major cause of disease in grazing livestock; however, individual animals differ in their response to infection. To identify genes whose expression correlates with resistance status, transcriptional profiling of resistant and susceptible sheep was undertaken. Transcription profiles were taken at three time points during the growth of lambs. The number of genes differentially expressed increased as animals were exposed to longer nematode challenge. Almost 300 genes, with a variety of functions, were differentially expressed overall, although genes more highly expressed in resistant animals typically had major histocompatibility complex (MHC) II, free radical scavenging or smooth muscle-specific functions. The Ovar-DQA1 gene was 8.4-fold more highly expressed in resistant animals. This was due in part to a higher frequency of DQA1 null alleles in susceptible animals. The null allele of DQA1 was also associated with susceptibility in a separate selection flock, presenting the hypothesis that failure to present parasite antigens to immune cells led to nematode susceptibility. To test this hypothesis, commercial rams from three breeds were genotyped for the null allele of DQA1. The homozygous null allele was associated with susceptibility in only one of the three breeds tested indicating that the null allele does not cause susceptibility to intestinal parasites per se but is probably in linkage disequilibrium with additional polymorphisms in the MHC region. A combination of these polymorphisms may contribute to susceptibility in some populations. The extent of linkage disequilibrium between polymorphisms may vary from breed to breed or population to population.
Development of two novel benzoylphenylurea sulfur analogues and evidence that the microtubule-associated protein tau is predictive of their activity in pancreatic cancer
Authors: Jimeno Antonio , Hallur Gurulingappa , Chan Audrey , Zhang Xiangfeng , Cusatis George , Chan Fonda , Shah Preeti , Chen Rongbing , Hamel Ernest , Garrett-Mayer Elizabeth , Khan Saeed , Hidalgo Manuel
Published: May 2007

In this work, we evaluated two lead compounds, referred to as SG410 and SG430, obtained from a screen of sulfur benzoylphenylurea analogues, against in vitro and in vivo models of pancreas cancer. Both drugs showed a similar mechanism of action profile, with SG410 being more potent as an inhibitor of tubulin assembly. We determined the best in vivo administration schedule and tested SG410 and SG430 in nine cases of a novel platform of direct pancreas cancer xenografts. Both compounds had antiproliferative activity in vitro in the low nanomolar range, but only SG410 showed significant activity in vivo. Administration of SG410 resulted in significant tumor growth delay in five of nine groups tested. In a direct comparison in three of the cases, SG410 was at least as efficacious as docetaxel. We also sought markers that would be predictive of the efficacy of these agents, and we found such a marker in microtubule-associated protein tau (MAPT). This protein enhances the assembly and stability of microtubules. In both the cell lines and the direct human xenografts, MAPT mRNA and protein levels correlated well. There was also a statistically significant inverse correlation between MAPT expression and sensitivity to the tested agents. In summary, the novel sulfur benzoylphenylurea SG410 showed activity inversely related to MAPT expression in a preclinical model of pancreatic cancer comparable with that observed with docetaxel, another microtubule-targeting agent. [Mol Cancer Ther 2007;6(5):1509–16]
Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors
Authors: Kurmasheva Raushan T. , Harwood Franklin C. , Houghton Peter J.
Published: May 2007

Levels of vascular endothelial growth factor (VEGF) are regulated, in part, through activation of the phosphatidylinositol 3′-kinase/Akt pathway. Using pharmacologic inhibitors, we have examined the relative contributions of Akt and mammalian target of rapamycin (mTOR) signaling to VEGF production in neuroblastoma and rhabdomyosarcoma cells growing under normoxic (21% O2) or hypoxic (1% O2) conditions. Exogenous VEGF stimulated both Akt and extracellular signal–regulated kinase 1/2 phosphorylation in six of seven rhabdomyosarcoma cell lines but in only one of seven neuroblastoma cells, suggesting autocrine stimulation predominantly in rhabdomyosarcoma cell lines. In general, under normoxic conditions, neuroblastoma cells produced more VEGF (120–1,180 pg/106 cells/24 h) compared with rhabdomyosarcoma lines (0–200 pg/106 cells/24 h). Rapamycin, a selective inhibitor of mTOR, reduced VEGF production in rhabdomyosarcoma cells under normoxic conditions and partially suppressed hypoxia-driven increases in VEGF. However, it poorly inhibited VEGF production under either condition in the majority of neuroblastoma cell lines despite inhibition of mTOR signaling. Rapamycin failed to modulate levels of hypoxia-inducible factor 1α (HIF-1α) under normoxic conditions and modestly reduced hypoxia-driven increases in HIF-1α only in rhabdomyosarcoma cells. In contrast to rapamycin, inhibition of Akt by A-443654 completely blocked signaling to glycogen synthase kinase 3β and had more dramatic effects on VEGF production. Notably, A-443654 significantly inhibited VEGF production in rapamycin-refractory neuroblastoma cell lines. Importantly, whereas combining A-443654 with rapamycin had variable effect on cell proliferation, the combination essentially blocked hypoxia-driven increases in VEGF in all cell lines examined, suggesting that dual blockade at different levels in the phosphatidylinositol 3′-kinase–initiated signaling pathway may be a reasonable strategy for preventing VEGF production in cancer cells derived from pediatric solid tumors. However, this will require formal testing in vivo using animal models of childhood cancer. [Mol Cancer Ther 2007;6(5):1620–8]
Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents
Authors: Yoshimoto Yasunori , Augustine Christina K. , Yoo Jin S. , Zipfel Patricia A. , Selim M. Angelica , Pruitt Scott K. , Friedman Henry S. , Ali-Osman Francis , Tyler Douglas S.
Published: May 2007

Five different human melanoma xenografts were used in a xenograft model of extremity melanoma to evaluate the variability of tumor response to regionally administered melphalan or temozolomide and to determine if various components of pertinent drug resistance pathways for melphalan [glutathione S-transferase (GST)/glutathione] and temozolomide [O6-alkylguanine DNA alkyltranferase (AGT)/mismatch repair (MMR)] could be predictive of tumor response. Xenograft-bearing rats underwent regional isolated limb infusion with either melphalan (90 mg/kg) or temozolomide (2,000 mg/kg). The levels of AGT activity, GST activity, glutathione level, and GST/AGT expression were examined in this group of xenografts and found to be quite heterogeneous. No correlation was identified between melphalan sensitivity and the GST/glutathione cellular detoxification pathway. In contrast, a strong correlation between the levels of AGT activity and percentage increase in tumor volume on day 30 (r = 0.88) was noted for tumors treated with temozolomide. Regional therapy with temozolomide was more effective when compared with melphalan for the xenograft with the lowest AGT activity, whereas melphalan was more effective than temozolomide in another xenograft that had the highest AGT activity. In three other xenografts, there was no significant difference in response between the two chemotherapy agents. This study shows that AGT activity may be useful in predicting the utility of temozolomide-based regional therapy for advanced extremity melanoma tumors. Our observations also point out the limited ability of analysis of the GST/glutathione pathway to predict response to chemotherapies like melphalan whose resistance is primarily mediated through a complex mechanism of detoxification. [Mol Cancer Ther 2007;6(5):1492–500]
MicroRNA expression profiles for the NCI-60 cancer cell panel
Authors: Blower Paul E. , Verducci Joseph S. , Lin Shili , Zhou Jin , Chung Ji-Hyun , Dai Zunyan , Liu Chang-Gong , Reinhold William , Lorenzi Philip L. , Kaldjian Eric P. , Croce Carlo M. , Weinstein John N. , Sadee Wolfgang
Published: May 2007

Advances in the understanding of cancer cell biology and response to drug treatment have benefited from new molecular technologies and methods for integrating information from multiple sources. The NCI-60, a panel of 60 diverse human cancer cell lines, has been used by the National Cancer Institute to screen >100,000 chemical compounds and natural product extracts for anticancer activity. The NCI-60 has also been profiled for mRNA and protein expression, mutational status, chromosomal aberrations, and DNA copy number, generating an unparalleled public resource for integrated chemogenomic studies. Recently, microRNAs have been shown to target particular sets of mRNAs, thereby preventing translation or accelerating mRNA turnover. To complement the existing NCI-60 data sets, we have measured expression levels of microRNAs in the NCI-60 and incorporated the resulting data into the CellMiner program package for integrative analysis. Cell line groupings based on microRNA expression were generally consistent with tissue type and with cell line clustering based on mRNA expression. However, mRNA expression seemed to be somewhat more informative for discriminating among tissue types than was microRNA expression. In addition, we found that there does not seem to be a significant correlation between microRNA expression patterns and those of known target transcripts. Comparison of microRNA expression patterns and compound potency patterns showed significant correlations, suggesting that microRNAs may play a role in chemoresistance. Combined with gene expression and other biological data using multivariate analysis, microRNA expression profiles may provide a critical link for understanding mechanisms involved in chemosensitivity and chemoresistance. [Mol Cancer Ther 2007;6(5):1483–91]
p53 therapy in a patient with Li-Fraumeni syndrome
Authors: Senzer Neil , Nemunaitis John , Nemunaitis Michael , Lamont Jeffrey , Gore Martin , Gabra Hani , Eeles Rosalind , Sodha Nayanta , Lynch Frank J. , Zumstein Louis A. , Menander Kerstin B. , Sobol Robert E. , Chada Sunil
Published: May 2007

Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy. [Mol Cancer Ther 2007;6(5):1478–1482
Physiology and Pharmacology of the Human Ureter: Basis for Current and Future Treatments
Authors: Canda A. Erdem , Turna Burak , Cinar G. Mehtap , Nazlı Oktay
Published: May 2007

Introduction: This article sets out to be a review regarding agents that affect contraction and relaxation of the ureter in order to establish a basis for current and future treatments for upper urinary tract obstruction. Material and Methods: A complete review of the English literature using MEDLINE was performed between 1960 and 2007 on ureter physiology and pharmacology with special emphasis on signal transduction mechanisms involved in the contractile regulation of the human ureter. Results: Activation of muscarinic and adrenergic receptors increases the amplitude of ureteral contractions. The sympathetic nerves modulate the contractions by α-adrenoceptors and relaxation by β-adrenoceptors. The purinergic system is important in sensory/motor functions and ATP is an important non-adrenergic non-cholinergic (NANC) agent causing contraction. Nitric oxide (NO) is a major inhibitory NANC neurotransmitter causing relaxation. Serotonin causes contraction. Prostaglandin-F2α contracts whereas prostaglandin-E1/E2 relaxes the ureter. Phosphodiesterases (PDE) and the Rho-kinase pathway have recently been identified in the human ureter. PDE-IV inhibitors, K+ channel openers, calcium antagonists, α1-adrenoceptor antagonists and NO donors seem to be promising drugs in relieving obstruction and facilitating stone passage. Conclusions: Further understanding of the ureteral function and pharmacology may lead to the discovery of promising new drugs that could be useful in relieving ureteral colic, facilitating spontaneous stone passage, preparing the ureter for ureteroscopy as well as acting adjunctive to extracorporeal shock-wave lithotripsy.
Impact of Additional Sampling in the TRUS-Guided Biopsy for the Diagnosis of Prostate Cancer
Authors: Stamatiou Konstantinos , Alevizos Alevizos , Karanasiou Vasilisa , Mariolis Anargiros , Mihas Constantinos , Papathanasiou Marek , Bovis Konstantinos , Sofras Frangiskos
Published: May 2007

Aim: To evaluate the diagnostic value of 10+ systematic sampling technique when performing transrectal ultrasound-guided (TRUS) prostate biopsy, compared with the sextant biopsy technique for patients with suspected prostate cancer. Methods: 286 patients with suspected prostate cancer were included in the study. Patients were eligible for the study if they had serum levels of prostate-specific antigen (PSA) >4 ng/ml or ratio PSA <0.25 and/or an abnormal digital rectal examination (DRE). The population sample was divided in three groups: (1) those with positive PSA, PSA ratio and DRE (70 patients); (2) those with positive PSA and PSA ratio but normal DRE (178 patients), and (3) those with positive PSA and PSA ratio, positive PSA velocity and a negative biopsy in the previous 6-month period (38 patients). In addition to the conventional sextant prostate biopsy cores, four more biopsies were obtained from the lateral peripheral zone (10 core biopsy protocol). Additional cores (total of 12–14) were also randomly selected in case of larger prostates (>60 ml) or from suspicious foci revealed by transrectal ultrasound. All additional biopsy cores were submitted separately to the pathological department. Results: Cancer was detected in 55.7% (39/70) and 69% (48/70) of the patients (for sextant core and for the extended biopsy protocols, respectively) in the first study group, 11% (20/178) and 23% (41/178) of the patients (for the sextant and the extended biopsy protocols, respectively) in the second study group, and 42% (16/38) and 63% (24/38) of the patients (for the sextant and the extended biopsy protocols, respectively) in the third study group. The addition of the lateral peripheral zone (PZ) of the prostate to the sextant biopsy showed a 23, 105 and 50% increase in the number of cancers diagnosed in the first, second and third study groups, respectively. The improvement of cancer detection rate (sensitivity) was statistically significant for all groups evaluated. Conclusion: The 10+ systematic TRUS-guided prostate biopsy improves the detection rate of prostate cancer compared to the sextant biopsy technique alone, especially when performed in men with positive PSA, PSA ratio, and negative DRE.
Palliative Treatment of Bone Metastases in Hormone-Refractory Prostate Cancer: Effects of Pamidronate on the Carboxyterminal Telopeptide of Type-I Collagen Level in Patients with Increasing Prostate-Specific Antigen Levels
Authors: Kawashima Hidenori , Tanaka Tomoaki , Kuratsukuri Katsuyuki , Uchida Junji , Sugimura Kazunobu , Tamada Satoshi , Nishisaka Nobuyasu , Kumata Katsuyuki , Iwai Yoshihito , Ikemoto Shinichi , Ezaki Kazuyoshi , Nakatani Tatsuya
Published: May 2007

Purpose: Bisphosphonates have been reported to be effective in reducing bone pain and skeletal-related events associated with bone metastases in hormone-refractory prostate cancer (HRPC). However, whether bone resorption is reduced primarily by these particular drugs is difficult to evaluate because patients with HRPC are usually treated with secondary or tertiary hormonal manipulations including second-line antiandrogens, high-dose diethylstilbestrol, or low-dose dexamethasone therapies, some of which may also be effective. Thus, we assessed changes in the level of the carboxyterminal telopeptide of type-I collagen (ICTP), a bone resorption marker, before and after pamidronate administration in HRPC patients with increasing prostate-specific antigen (PSA) levels. Patients and Methods: Twenty-one HRPC patients with bone metastases and increasing PSA levels were intravenously treated with pamidronate at a dose of 30 mg either every 2 or every 4 weeks. Pamidronate administration was started immediately after confirmation of three consecutive increases in the PSA level. Results: In 14 patients (67%), the ICTP levels decreased after the administration of pamidronate, despite increasing PSA levels. In 7 of these cases, the ICTP levels were lower than those recorded for 6 months or longer before the start of pamidronate administration. The characteristics of the responders were compared with those of the non-responders. Conclusion: In 67% of the HRPC patients with increasing PSA levels, pamidronate reduced the accelerated turnover of bone metabolism caused by metastases of prostate cancer.
Protective Effects of Trimetazidine on Testicular Ischemia-Reperfusion Injury in Rats
Authors: Unal Dogan , Karatas Omer F. , Savas Murat , Yeni Ercan , Keser Bulent S. , Verit Ayhan , Erel Ozcan , Bitiren Muharrem
Published: May 2007

Introduction: We tried to prove the effectiveness of trimetazidine (TMZ) on testicular torsion-detorsion injury. Materials and Methods: 15 male rats were equally divided into three groups: group 1 was the sham-operated control group; group 2 had 2 h of unilateral testicular ischemia followed by 3 days of reperfusion, and group 3 had 2 h of unilateral testicular ischemia followed by 3 days of oral TMZ treatment (5 mg/kg, bid) during reperfusion. In the removed testicles, tissue reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), malondialdehyde (MDA) levels and pathological modified Johnson scores (MJS) were evaluated. Mann-Whitney U test was used for statistical evaluations. Results: In group 2, on the ipsilateral side, GSH were significantly lower and MDA were higher than in groups 1 and 3, though GSH and MDA were not statistically different between groups 1 and 3. On the other hand, GPx in the control testicles of group 3 was significantly lower compared to those in the counterparts of both groups 1 and 2. Among three groups, GR determined in both testicles were not statistically different. On the ipsilateral side, MJS in group 3 were lower than in the sham group, but significantly higher than in group 2. Conclusions: According to this study, TMZ has an antioxidant effect on testicular torsion-detorsion injury, though the protective effect of TMZ seems to decrease in control testicles. Consequently it has been considered that TMZ can be only used in torsion patients with a healthy contralateral testicle after further studies have been conducted.
Bilateral Percutaneous Nephrolithotomy in a Patient with Hemophilia A Disorder
Authors: Kural Ali Rıza , Demirkesen Oktay , Alici Bulent , Obek Can , Tunc Burcin , Ozkan Burak
Published: May 2007

A 50-year-old man with hemophilia A presented with recurrent hematuria due to renal stone disease. He was receiving approximately 50,000 units of recombinant factor (rF) VIII concentrate every year due to hematuria. Between 1996 and 2002, his serum creatinine level increased from 0.7 to 1.2 ng/ml. In an effort to resolve the problems of excessive blood loss with transfusions, recurrent rF VIII replacements and deteriorating renal function, he was offered treatment with percutaneous nephrolithotomy (PNL) in conjunction with rF VIII administration. He underwent left PNL for left staghorn calculi in November 2002 with administration of 52,000 units rF VIII, and another PNL for the right kidney in April 2004 with the administration of 90,500 units rF VIII. A pneumatic lithotriptor was used in both operations. The serum creatinine level was 0.8 ng/ml upon completion of treatment and the patient was symptom and stone free at 10-month follow-up. He has not suffered from hematuria since that time. We conclude that bleeding disorders may not be a contraindication for PNL if corrected and monitored appropriately.
Prevention of Abdominal Adhesions – Present State and What’s beyond the Horizon?
Authors: Tingstedt B. , Isaksson K. , Andersson E. , Andersson R.
Published: May 2007

Intra-abdominal adhesions are normally found after most surgical procedures. Many of the adhesions are asymptomatic, but in about 5% they will lead to readmission due to adhesion-related disorders, such as small bowel obstruction, pelvic pain and infertility. This review discusses possible ways to prevent abdominal adhesions and provides an update as comes to where we stand today in research regarding experimental and clinical use of various antiadhesive agents.
Smiling When Distressed: When a Smile Is a Frown Turned Upside Down
Authors: Ansfield Matthew E.
Published: May 2007

This research tested self-regulation and self-presentation as psychological mechanisms that motivate smiling when distressed. In Study 1, participants viewed moderately and intensely distressing, amusing, and neutral videos in social or nonsocial conditions. Smiling when distressed was most prevalent in conditions in which participants reported the greatest emotional distress. Specifically, while viewing distressing videos, men reported experiencing greater overall distress and also smiled more than women, especially in social conditions and while viewing intensely (as opposed to moderately) distressing stimuli. In general, smiling was related to more negative affect while viewing distressing videos but to more positive affect after viewing such stimuli. Study 2 explored raters' social perceptions of participants from Study 1, confirming that people judge distressed smilers as less socially appropriate and less likable than nonsmilers. Findings suggest that although distressed smiling serves a probable self-regulatory function, it may also bear some negative social consequences.
Psychosocial Mediation of Religious Coping Styles: A Study of Short-Term Psychological Distress Following Cardiac Surgery
Authors: Ai Amy L. , Park Crystal L. , Bu Huang  , Rodgers Willard , Tice Terrence N.
Published: May 2007

Although religiousness and religious coping styles are well-documented predictors of well-being, research on the mechanisms through which religious coping styles operate is sparse. This prospective study examined religious coping styles, hope, and social support as pathways of the influence of general religiousness (religious importance and involvement) on the reduced postoperative psychological distress of 309 cardiac patients. Results of structural equation modeling indicated that controlling for preoperative distress, gender, and education, religiousness contributed to positive religious coping, which in turn was associated with less distress via a path fully mediated by the secular factors of social support and hope. Furthermore, negative religious coping styles, although correlated at the bivariate level with preoperative distress but not with religiousness, were associated both directly and indirectly with greater post-operative distress via the same mediators.