bluuebunny/crossref_metadata_2025 huggingface dataset:
Voluntary physical exercise and coronary flow velocity reserve: a transthoracic colour Doppler echocardiography study in spontaneously hypertensive rats
Authors: Hägg Ulrika , Grönros Julia , Wikström Johannes , Jonsdottir Ingibjörg H. , Bergström Göran , Gan Li-ming
Published: August 2005

In the present study, we have developed and demonstrated a coronary artery imaging protocol in rats using transthoracic high-frequency CDE (colour Doppler echocardiography) to investigate the potential direct effects of exercise on CFVR (coronary flow velocity reserve). SHR (spontaneously hypertensive rats) performed voluntary exercise for 6 weeks. Rats were then submitted to ultrasonographic examination and CFVR measurements. The LAD (left anterior descending coronary artery) was visualized using transthoracic CDE in a modified parasternal long-axis view. Doppler measurement was made in mid-LAD during baseline and adenosine-induced hyperaemic condition. Gene and protein expression in cardiac tissue were studied using real-time PCR and immunohistochemistry. Adenosine infusion significantly (P<0.001, as determined by ANOVA) decreased HR, without affecting blood pressure in anaesthetized SHR. A significantly greater adenosine dose-dependent response was seen in exercised rats compared with controls (P=0.02, as determined by ANOVA). The baseline flow velocity in mid-LAD was 0.33±0.06 and 0.41±0.14 m/s in the exercised and control animals respectively (P value was not significant). The maximum adenosine-induced response was reached at a dose of 140 μg·kg−1 of body weight·min−1, and CFVR averaged at 2.6±0.53 and 1.5±0.24 in exercised and control animals respectively (P<0.01). Gene expression of CuZnSOD was up-regulated by 21% in exercised animals compared with controls (1.1±0.16 compared with 0.89±0.09; P<0.01), whereas eNOS expression was unchanged. In conclusion, CFVR in rats can be non-invasively assessed using CDE with high feasibility. Physical exercise is associated with improved CFVR and antioxidative capacity in SHR.
Failure of angiotensin II to suppress plasma renin activity in normotensive subjects with a positive family history of hypertension
Authors: Herlitz Hans , Palmgren Eva , Widgren Bengt , Aurell Mattias
Published: August 2005

The renin–angiotensin system is implicated in the pathophysiology of hypertension. Renin release is regulated by a number of factors, including circulating Ang II (angiotensin II), the so-called short feedback loop. The aim of the present study was to investigate the responsiveness of circulating Ang II on PRA (plasma renin activity) in normotensive subjects with a PFH or NFH (positive or negative family history of hypertension respectively). PRA, renal haemodynamics and urinary sodium excretion were measured during infusion of Ang II without and with pretreatment with the AT1 (Ang II type 1) receptor blocker irbesartan. Normotensive men with a PFH (n=13) and NFH (n=10), with a mean age of 38 years, were given on different occasions intravenous Ang II infusions of 0.1, 0.5 and 1.0 ng·kg−1 of body weight·min−1 before and after pretreatment with 150 mg of irbesartan once a day for 5 consecutive days. RPF (renal plasma flow) and GFR (glomerular filtration rate) were also measured. Before Ang II infusion, the PFH and NFH groups did not differ with respect to BP (blood pressure), body mass index, PRA, RBF (renal blood flow) or urinary sodium. There was no difference in BP or renal haemodynamic response to the highest Ang II dose between the groups. PRA declined with the highest Ang II dose (P<0.01) in subjects with a NFH, but not in subjects with a PFH. After treatment with irbesartan when Ang II had no effect on BP in either group, Ang II also suppressed PRA in subjects with a PFH (P<0.01), and the difference between the groups at baseline was thus eliminated. In conclusion, these findings indicate that subjects with a PFH have a defective Ang II suppression of PRA, which is corrected by AT1 receptor blockade.
Coronary flow responses to exercise training: further evidence of the benefit of an underutilized therapeutic modality
Authors: Marwick Thomas H.
Published: August 2005

Inactivity is associated with endothelial dysfunction and the development of cardiovascular disease. Exercise training has a favourable effect in the management of hypertension, heart failure and ischaemic heart disease. These beneficial effects are probably mediated through improvements of vascular function and, in this issue of Clinical Science, Hägg and co-authors propose a coronary artery effect. The use of a Doppler technique for non-invasive assessment of coronary flow reserve in a small animal model is an exciting aspect of this study. If feasible in the hands of other investigators, the availability of sequential coronary flow measurements in animal models may help improve our understanding of the mechanisms of disorders of the coronary circulation.
Are dipolar liquids ferroelectric?
Authors: Shelton David P.
Published: August 2005

VH and HV depolarized hyper-Rayleigh scattering spectra were measured for liquid solutions of dipolar CH3CN in nondipolar C2Cl4 at T=300K. The VH spectrum contains a strong narrow peak due to a slowly relaxing longitudinal orientation mode. This peak is absent in the HV spectrum, and it disappears from the VH spectrum when the CH3CN concentration is reduced to 8%. This observation is consistent with a ferroelectric phase transition predicted to occur when ρμ02=9ε0kT=49D2M.
Substrate dependence of the magneto-optic properties of Co nanoparticles
Authors: Kalska B. , Schwinge K. , Paggel J. , Fumagalli P. , Hilgendorff M. , Giersig M.
Published: August 2005

We present results from magneto-optic studies of 10-nm Co nanoparticles on various substrates at room temperature. The magneto-optic properties in connection with substrate composition and morphology are discussed. A strong influence of the substrate composition on the polar Kerr rotation is observed which is mainly due to optical properties of the substrate material such as the plasma edge. The influence of the morphology on the magneto-optic properties can be qualitatively explained by discussing the interplay between the Co nanoparticles and reflected as well as scattered components of the light. These findings are corroborated by atomic-force microscopy. Auger-electron spectra confirm a strong influence of oxidation on the magneto-optic response.
Photoemission studies on niobium for superconducting photoinjectors
Authors: Smedley J. , Rao T. , Zhao Q.
Published: August 2005

This work presents an investigation of the photoemission properties of niobium. The quantum efficiency (QE) of niobium cathodes was measured for a variety of surface preparations relevant to the operation of a superconducting injector. The dependence of the QE on wavelength, applied field, and laser cleaning energy was determined. The three-step model of photoemission was adapted to fit the observed emission behavior. QE values of 6.5×10−5 for 266 nm, 1.0×10−4 for 248 nm, and 2.8×10−4 for 193 nm were observed with a bias field of 1MV∕m.
High-precision measurement of azimuthal rotation of liquid crystals on solid substrates
Authors: Jánossy I.
Published: August 2005

A high-accuracy optical method for the determination of the rotation of the liquid-crystal director on solid substrates is reported. The measurements involve the use of a photoelastic modulator in conjunction with a white light source. The detection of the first and second harmonics of the light signal allows for the determination both of the director position and the twist deformation at the exit face of the cell. The method is illustrated by experiments on the liquid crystal penthylcyanobiphenyl aligned by polyimide layers. The importance of director gliding is pointed out as well.
Activation energies for Te and Be in metamorphically grown AlSb and InxAl1−xSb layers
Authors: Hill P. , Weisse-Bernstein N. , Dawson L. R. , Dowd P. , Krishna S.
Published: August 2005

The activation energies of tellurium and beryllium in InxAl1−xSb grown by solid-source molecular beam epitaxy on semi-insulating GaAs substrates are reported. Temperature-dependent Hall measurements of carrier concentration show that while the activation energy of beryllium is relatively low for all compositions (EA<32meV), the activation energy of tellurium is highly dependent on composition and appears to form a deep level donor state (ED>100meV) in the composition range between approximately 0.1<x<0.4. For compositions outside this range, significantly reduced Te activation energies (ED<44meV) are obtained. The ability to dope InxAl1−xSb beyond the deep-donor range has been demonstrated by fabricating a p-i-n diode from In0.50Al0.50Sb, with a turn-on voltage of ∼0.4V and a forward series resistance of 0.64Ω.
Experimental investigation of an atmospheric photoconductively switched high-voltage spark gap
Authors: Hendriks J. , Broks B. H. P. , van der Mullen J. J. A. M. , Brussaard G. J. H.
Published: August 2005

We report on the experimental investigation of the photoconductively switched gas-filled spark gap. When the laser intensity of a femtosecond laser is high enough (around 1018Wm−2), a plasma can be created that spans the complete distance between the electrodes. The gas-filled spark gap is then closed on a femtosecond time scale, similar to photoconductive switching of a semiconductor switch. Stochastic breakdown processes, such as avalanche and streamer formation that cause the breakdown in laser triggered spark gaps, are passed over, which results in faster rise time and less jitter. Measurements of the switched pulses as a function of laser energy were performed in a 1-mm gap at an applied voltage of 4.5 kV. A clear transition from triggering to switching was measured with increased laser energy. Measurements of the output pulses with the gap filled with nitrogen at 1 atm showed results very similar to measurements in air in the same gap. In the switching regime, the amplitude of the switched pulse did not depend strongly on the laser energy. Measurements at lower applied voltages but with the same gap distance showed that it was possible to switch voltages as low as 10% of the self-breakdown voltage. At low applied voltages, a significant difference between the applied voltage and the output voltage is measured. A possible explanation is given based on the dynamic behavior of the laser-created plasma. The measured rise time and jitter of the switched pulses were both below the resolution of the measurement equipment, i.e., better than 100 and 15 ps, respectively.
High efficiency and brightness of blue light emission from dislocation-free InGaN∕GaN quantum well nanorod arrays
Authors: Sun Yuanping , Cho Yong-Hoon , Kim Hwa-Mok , Kang Tae Won
Published: August 2005

We report on the optical properties of blue-light-emitting, dislocation-free InGaN∕GaN multiple quantum well (MQW) nanorod arrays (NRAs) with high brightness and high efficiency. The InGaN MQW NRAs were grown by metal-organic hydride vapor phase epitaxy and the optical properties were investigated in detail by photoluminescence (PL), PL excitation (PLE) and time resolved PL. We observed a large Stokes-like shift between InGaN PL emission and PLE absorption edge due to the influence of built-in internal electrical field, reflecting the coherent growth of MQW along the NRA growth direction. From the temperature-dependent PL, we extracted a PL intensity ratio at 300to15K of ∼55.4% and large thermal activation energy of ∼171meV from the InGaN∕GaN MQW NRAs. Time-resolved PL results showed almost the same decay time of the InGaN emission at 20 and 300K. From the results, the optical properties are dominated by the radiative recombination process and are insensitive to temperature due to large thermal activation energy, indicating that carriers in InGaN wells are well confined by the GaN barriers without an influence of other non-radiative processes. Therefore, we conclude that internal quantum efficiency and extraction efficiency of MQW NRAs are significantly enhanced by a drastic suppression of non-radiative centers inside NRAs and a large surface area to active volume area ratio of NRAs, respectively.
Suburbanisation, Employment Change, and Commuting in the Tallinn Metropolitan Area
Authors: Tammaru Tiit
Published: August 2005

The author's aim is to analyse the role of suburbanisation and employment change in commuting in the Tallinn metropolitan area, Estonia. The author analyses changes in commuting compared with the late Soviet period, and clarifies the compositional differences between commuters and noncommuters. Data analysis is based on anonymous, individual, 2000 Census records, and bivariate and multivariate methods are employed. The major conclusions are that the commuting field of Tallinn enlarged and the intensity of commuting from the suburbs to Tallinn increased in the 1990s. Commuters differ from noncommuters both in Tallinn and in the suburbs in regard to most of the social, demographic, and housing variables studied. People who suburbanised in the 1990s were more likely to be commuters than were people who already lived in the suburbs at the end of the Soviet period; high-unemployment areas did not send more commuters to Tallinn than did low-unemployment areas.
Migration and the Regional Redistribution of Nonearnings Income in the United States: Metropolitan and Nonmetropolitan Perspectives from 1975 to 2000
Authors: Nelson Peter B
Published: August 2005

Many advanced economies have an aging population that relies heavily on government pensions, social security, and privately held investment-based income. In the United States the geography of social security and investment income (collectively called nonearnings income) is uneven. Furthermore, the ways in which migration serves to redistribute such income across space remain unstudied. This paper highlights regions in the United States that are becoming increasingly attractive to nonearnings income through migration. Overall, there is a consistent Rustbelt-to-Sunbelt shift in nonearnings income due to migration. These income shifts, however, are quite distinct between metropolitan and nonmetropolitan areas. Starting in the late 1980s, nonmetropolitan portions of the Rustbelt enjoyed net gains in nonearnings income through migration processes. Therefore, it appears that the migration systems which drew income away from the nonmetropolitan north during the 1970s are now shifting to some degree. Analysis further indicates that migration contributes to greater levels of economic disparity across space. Whereas flows of social security income are highly influenced by the aggregate level of migration, flows of investment income are more influenced by differentials in migrants' per capita income levels. Regions such as the Plains are attracting migrants with relatively low per capita nonearnings income whereas the Rocky Mountain and New England regions are attracting individuals with high per capita income. Destinations such as the Rocky Mountains and New England are likely to enjoy significant economic benefits as new sources of income arrive which are tied to migration, but the Plains region is left with less-well-off populations, which pose significant social and economic problems in such sending regions. As the population in the United States and other advanced economies ages, these processes of nonearnings income migration become increasingly important in shaping local and regional economic conditions.
Community Currency in the United States: The Social Environments in Which it Emerges and Survives
Authors: Collom Ed
Published: August 2005

Community currency originated as a means to empower the economically marginalized. This paper studies the US population of community currency systems using locally printed money. Eighty-two systems are identified that have been attempted in the United States since 1991. Internet searches and contact with system coordinators indicate that only 20.7% of all systems are active. Regions in which they occur are described; more than one quarter are in Pacific states. City-level Census 2000 data are employed in analyses of environmental conduciveness to determine in which types of social environments local currencies emerge and survive within. Social movement theory is engaged to identify general, population-based resources for local movements. Economic marginality and labor-market-independence hypotheses are also formulated and tested. The major findings indicate that cities with local currencies are characterized by populations with lower household incomes, higher poverty rates, higher unemployment rates, and larger self-employment sectors. Evidence is also presented indicating that community currencies tend to survive in places with younger populations, higher educational attainment, fewer married people, and less residential stability. Implications concerning the future of the community currency movement and its ability to empower the marginalized are drawn.
Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene
Authors: Mogil Jeffrey S. , Miermeister Frank , Seifert Frank , Strasburg Kate , Zimmermann Katharina , Reinold Heiko , Austin Jean-Sebastien , Bernardini Nadia , Chesler Elissa J. , Hofmann Heiko A. , Hordo Christian , Messlinger Karl , Nemmani Kumar V. S. , Rankin Andrew L. , Ritchie Jennifer , Siegling Angela , Smith Shad B. , Sotocinal Susana , Vater Axel , Lehto Sonya G. , Klussmann Sven , Quirion Remi , Michaelis Martin , Devor Marshall , Reeh Peter W.
Published: August 2005

Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the
Calca
gene that codes for CGRPα.
An Early Cambrian problematic fossil:Vetustovermisand its possible affinities
Authors: Chen Jun-yuan , Huang Di-ying , Bottjer David J
Published: August 2005

The Early Cambrian problematic fossilVetustovermis(Glaessner 1979Alcheringa3, 21–31) was described as an annelid or arthropod. Anatomical analysis of 17 new specimens from the Lower Cambrian Maotianshan Shale at Anning, Kunming (South China) does not support its affinities with annelids or arthropods. Anatomical features instead resemble other animal groups including modern flatworms, nemertines and molluscs. The presence of a pelagic slug-like form and ventral foot, as well as a head with eyes and tentacles indicates a possible affinity with molluscs, but these characters are not present only in molluscs; some of them are shared with other animal groups, including flatworms and nemertines. For example, a ventral foot-like structure is found in nemertines, ‘turbellarians’, and some polychaete groups. The well differentiated head is seen in separate bilaterian groups, but among molluscs it did not occur before the evolutionary level of the Conchifera. Unlike the ctenia-gills in molluscs, the gills inVetustovermisare bar-like. All the characters displayed in this 525 million-year old soft-bodied animal fail to demonstrate clear affinity with molluscs or any other known extant or extinct animal groups, but argue for representing an independently evolved animal group, which flourished in Early Cambrian and possibly in Middle Cambrian time.
ALTERED LEVEL OF APURINIC/APYRIMIDINIC ENDONUCLEASE/REDOX FACTOR‐1 (APE/Ref‐1) mRNA IN THE HIPPOCAMPUS OF OVARIECTOMIZED RATS TREATED BY RALOXIFENE AGAINST KAINIC ACID
Authors: Yalcin Ayfer , Kanit Lutfiye , Durmaz Guliz , Sargin Sehnaz , Terek Cosan H , Tanyolac Bahattin
Published: August 2005

1. Accumulated clinical evidence suggests that selective oestrogen receptor modulators (SERM), such as raloxifene, may be neuroprotective. Oxidative stress is a likely molecular mechanism in the neurotoxicity of kainic acid (KA), an excitotoxic substance. The expression levels of the apurinic/apyrimidinic endonuclease/redox factor‐1 (APE/Ref‐1) gene seem to correlate with cellular sensitivity to reactive oxygen species (ROS) and a reduction in the expression of APE/Ref‐1 may cause oxidative DNA damage.

2. The aim of the present study was to assess the effects of KA and raloxifene on the level of APE/Ref‐1 mRNA in the hippocampus of ovariectomized rats. The expression of the APE/Ref‐1 gene was quantified using reverse transcription followed by real‐time polymerase chain reaction.

3. The results show that the level of APE/Ref‐1 mRNA increased significantly in raloxifene‐treated rats. However, raloxifene treatment did not affect the seizure severity induced by KA. We also observed that raloxifene treatment against simultaneous KA injection maintained the increased level of APE/Ref‐1 mRNA in the hippocampus.

4. Therefore, the results of the present study seem to support previous data suggesting the potential significance of raloxifene in neuroprotection.
OXIDATIVE DAMAGE TO NUCLEAR DNA IN STREPTOZOTOCIN‐DIABETIC RAT LIVER
Authors: Andican Gülnur , Burçak Gülden
Published: August 2005

1. Accumulating evidence suggests that oxidative and glycative stress is enhanced in diabetes. Oxidative stress induces DNA damage. In the present study, we assessed the 8‐oxo‐2′‐deoxyguanosine (8‐oxodG) content of DNA, an indicator of oxidative DNA damage, in streptozotocin (STZ)‐induced diabetic (n = 21) and control rats (n = 18).

2. Rats were rendered diabetic by intraperitoneal administration of STZ at a dose of 65 mg/kg. Glucose was determined by glucose oxidase and glycated haemoglobin (GHb), an indicator of glycative stress, was determined by agarose‐boronate affinity chromatography. 8‐Oxo‐2′‐deoxyguanosine within the DNA (ratio of 8‐oxodG to deoxyguanosine (dG)) was assessed by HPLC in conjunction with both electrochemical (8‐oxodG) and diode array (dG) detection.

3. Glucose, GHb and the extent of oxidative DNA damage in the liver of STZ‐diabetic rats were much higher compared with control rats. There was a correlation between GHb and 8‐oxodG/105 dG levels in control (r = 0.756, P < 0.001) and diabetic groups (r = 0.468, 0.02 < P < 0.05).

4. These results clearly show that oxidative damage to hepatic nuclear DNA increases in the diabetic state and that this increase is correlated with glycative stress.
HYPOTHALAMIC ANTIHYPERTENSIVE EFFECT OF METOPROLOL IN CHRONIC AORTIC COARCTATED RATS
Authors: Höcht Christian , Opezzo Javier AW , Taira Carlos A
Published: August 2005

1. The aim of the present study was to investigate the possible hypothalamic antihypertensive effect of metoprolol and its action on aminergic neurotransmission in sham‐operated (SO) rats and aortic coarctated (ACo) rats at a chronic hypertensive stage using the microdialysis technique.

2. Hypothalamic metoprolol concentrations and their cardiovascular effects were measured after the intravenous administration of 3 mg/kg metoprolol. Based on metoprolol concentrations reached in the anterior hypothalamus, in a second experiment the anterior hypothalamus of SO and ACo animals was perfused with Ringer's solution containing approximately 7.5 µg/mL metoprolol. The cardiovascular effects of metoprolol perfusion and changes in hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5‐hydroxyindol acetic acid (5‐HIAA) levels were measured during the perfusion.

3. After i.v. administration of metoprolol, a greater hypotensive effect was observed in ACo rats than in SO animals (Δ mean arterial pressure (MAP) −23.8 ± 2.1 vs−13.8 ± 1.3 mmHg, respectively; n = 5 for both groups). Metoprolol rapidly reached the central nervous system (CNS) in both groups of rats and its levels were similar in SO and ACo rats. Intrahypothalamic perfusion with metoprolol induced a significative decrease in blood pressure in ACo animals (ΔMAP −13.3 ± 1.5 mmHg; n = 5; P < 0.05 vs Ringer perfusion), but not in SO rats (ΔMAP 3.4 ± 2.7 mmHg; n = 5). Metoprolol perfusion reduced hypothalamic levels of DOPAC in ACo rats (65 ± 7% of basal levels; n = 5; P < 0.05 vs Ringer perfusion), but not in SO animals (87 ± 5% of basal levels; n = 5). There were no changes in hypothalamic concentrations 5‐HIAA observed in either experimental group.

4. In conclusion, metoprolol exerts a greater hypotensive effect in chronic ACo animals, suggesting a participation of β‐adrenoceptors in the maintenance of the hypertensive stage. Metoprolol distribution in the CNS is not affected by ACo. The hypotensive effect of metoprolol perfusion in ACo rats suggested that hypothalamic β‐adrenoceptor blockade is part of the antihypertensive effect of metoprolol in chronic ACo rats. The effects of metoprolol on DOPAC levels suggest a reduction of dopamine turnover in hypertensive animals, but not in SO rats.
Systematics of the olive thrush Turdus olivaceus species complex with reference to the taxonomic status of the endangered Taita thrush T. helleri
Authors: Bowie Rauri C. K. , Voelker Gary , Fjeldså Jon , Lens Luc , Hackett Shannon J. , Crowe Timothy M.
Published: August 2005

During the last 40 years, few species of African birds have undergone more taxonomic revision than the olive thrush Turdus olivaceus. This is due to disagreement on how to partition the striking phenotypic variation among allopatric populations. The current consensus is to recognise one species T. olivaceus, split into three assemblages: (1) the olivaceus group restricted to southern Africa, (2) the swynnertoni group of the Zimbabwean and southern Malawi highlands, and (3) the abyssinicus group of the montane highlands of eastern and central Africa. Mitochondrial DNA sequences from 63 individuals were analysed to investigate the phylogenetic relationships among 16 taxa (species and subspecies) in the olivaceus species complex (plus seven outgroup species), with, particular emphasis on the relationships and taxonomic status of the endangered Taita thrush (helleri). Phylogenetic hypotheses generated using parsimony, maximum likelihood, and Bayesian inference identified a number of discrete clades corresponding to recognised subspecies. Northern (abyssinicus clade) and southern populations (olivaceus+swynnertoni clade) of olive thrush differ by 9–10% in sequence divergence. Furthermore, all analytical methods suggested that helleri (Taita Hills) and roehli (Usambara and Pare Mountains) are reciprocally monophyletic with respect to mtDNA, and 2.5 to 10.5% divergent from all other forms of olive thrush. Both helleri and roehli are surrounded in adjacent highlands by populations of olive thrush that represent a more recent radiation, suggesting that helleri and roehli may be relict taxa which have been able to maintain their genetic integrity. The results of this study support previous arguments for recognizing the arid/woodland T. smithi as a species distinct from other southern African forest populations of T. olivaceus (including the swynnertoni group). Results further suggest that T. abyssinicus, T. helleri, and T. roehli be accorded species rank.
Increased Expression of trk Proto‐oncogene by γ‐Interferon in Human Neuroblastoma Cell Lines
Authors: Shikata Akane , Sugimoto Tohru , Hosoi Hajime , Sotozono Yasuhiro , Shikata Takuma , Sawada Tadashi , Parada Luis F.
Published: August 2005

Three human neuroblastoma cell lines were examined to determine the effect of recombinant γ‐interferon (IFN‐γ) treatment on the expression of trk proto‐oncogene. Increased levels of trk proto‐oncogene mRNA were observed in two neuroblastoma cell lines (KP‐N‐RT and KP‐N‐SI(FA)) after IFN‐γ treatment. The levels of trk mRNA increased with growth inhibition and morphological change in a time‐ and dose‐dependent manner. The decreased level of N‐myc mRNA after IFN‐γ‐treatment in KP‐N‐RT was inversely correlated with trk mRNA. Our results suggest that IFN‐γ can modulate the signal transduction of nerve growth factor in human neuroblastoma cells.
In vivo Efficacy of Neocarzinostatin Coupled with Fab Human/Mouse Chimeric Monoclonal Antibody A7 against Human Colorectal Cancer
Authors: Yamaguchi Toshiharu , Tsurumi Hiroshi , Kotani Tatsuya , Yamaoka Nobuki , Otsuji Eigo , Kitamura Kazuya , Takahashi Toshio
Published: August 2005

The anticancer polypeptide neocarzinostatin (NCS) was covalently coupled to a human/mouse chimeric Fab A7 monoclonal antibody (chFabA7) and the in vivo efficacy of this conjugate was examined. NCS concentration assay was carried out, and acute toxicity and tumoricidal effects were examined. The concentration assay, using anti‐NCS monoclonal antibody, revealed that administration of the chA7Fab conjugate leads to a greater blood retention and a higher tumor accumulation of NCS, when compared to free NCS administration. The tumoricidal effect of chA7Fab‐NCS was higher than that of either free NCS or the saline control, against antigen‐positive tumors. In antigen‐negative tumors there was no difference in toxic effect among the three preparations. Values of LD50, reflecting acute toxicity, were 5050 U/kg and 3600 U/kg for the chA7Fab‐NCS and the free NCS, respectively. These results suggest that chFahA7‐NCS may be a promising tool for targeting cancer chemotherapy.
A New Serum Tumor Marker, CAM 123‐6, Highly Specific to Pulmonary Adenocarcinoma
Authors: Hamada Hironobu , Kohno Nobuoki , Hiwada Kunio
Published: August 2005

KL‐6, a circulating mucin‐like glycoprotein, is a pulmonary adenocarcinoma‐associated antigen and is also regarded as an indicator of disease activity of interstitial pneumonitis. KL‐6 has extensive heterogeneous antigenic determinants and consists of multiple heterogeneous antigen molecules. We have searched for circulating KL‐6‐associated glycoproteins with superior diagnostic value to KL‐6 as a tumor marker for pulmonary adenocarcinoma. A new murine monoclonal antibody EH‐123 reacting with an asialosugar chain on KL‐6 was established. A new KL‐6‐associated molecule detected by a bimonoclonal bideterminant sandwich assay using the EH‐123 antibody as a catcher and horseradish peroxidase‐labeled KL‐6 as a tracer was designated as CAM 123‐6. In 59% (22 of 37) of patients with pulmonary adenocarcinoma, serum levels of CAM 123‐6 were abnormally elevated and the positive rate increased with the progression of clinical stage. Elevated levels were not detected in normal individuals or in patients with benign lung diseases, other histologic types of lung cancer, gastric cancer, colon cancer or breast cancer. CAM 123‐6 was more specific to pulmonary adenocarcinoma than carcinoembryonic antigen (CEA), but the sensitivity of CAM 123‐6 for pulmonary adenocarcinoma was similar to that of CEA. CAM 123‐6 is a promising candidate as a serum tumor marker for pulmonary adenocarcinoma.
Incidence of Second Primary Cancers in Osaka Residents, Japan, with Special Reference to Cumulative and Relative Risks
Authors: Tsukuma Hideaki , Fujimoto Isaburo , Hanai Aya , Hiyama Tomohiko , Kitagawa Takako , Kinoshita Noriko
Published: August 2005

This study was conducted to examine the incidence rates and cumulative risks of second primary cancers in Osaka and to compare the observed number of second primary cancers with the expected number calculated using cancer incidence rates among Osaka residents. Study subjects were all reported cases aged 0–79 who were first diagnosed as having a first primary cancer between 1966–86. Incidence of second primary cancer among the study subjects was examined through to the end of 1989. The total number of study subjects was 217,307. During the follow‐up period (mean duration: 3.7 years), second primary cancers developed in 5,071 patients (2.3%). Incidence of synchronous (interval <3 months) and metachronous (interval ≥ 3 months) second primary cancers increased in the later years. Incidence rates of second primary cancers were significantly associated with gender (male), age and calendar year at diagnosis of the first cancer. Based on the incidence rates, cumulative risk of developing metachronous second primary cancer was calculated. The ten‐year cumulative risk was estimated as 10% for those who developed their first cancer during their sixties in 1978–83. The observed number of second primary cancers (including synchronous) was compared with the expected number. The ratios of observed‐to‐expected numbers were generally lower than 1.0 among those who developed their first cancer in 1966–77, while these ratios were higher than 1.0 among those who developed their first cancer in 1978–86. The ratios were much higher than 1.0 among those who developed their first cancer in their childhood and youth. Patients who had developed cancer of the colon, larynx, lung, bladder, or breast (female) showed significantly higher risk of developing second primary cancer during the period 1–4 years after diagnosis of the first cancer.
Expression of Sulfated Carbohydrate Chains Detected by Monoclonal Antibody 91.9H in Human Gastric Cancer Tissues
Authors: Ohe Yasuo , Hinoda Yuji , Irimura Tatsuro , Imai Kohzoh , Yachi Akira
Published: August 2005

Expression of sulfated carbohydrate chains in intestinal metaplasia (IM) and gastric cancer tissues was immunohistochemically evaluated by using a monoclonal antibody (MAb) 91.9H. While normal gastric tissues were negative for MAb 91.9H, IM and cancer tissues were positively stained with high frequency. The incidence was 67% for IM with chronic gastritis (n = 12), 95% for IM with gastric cancer (n=21), 77% for well and moderately differentiated adenocarcinomas (n = 13), 48% for poorly differentiated adenocarcinoma (n = 23), 89% for signet‐ring cell carcinoma (n = 9) and 100% for mucinous adenocarcinoma (n = 7). When poorly differentiated adenocarcinoma cases were divided into two groups, solid (n = 13) and non‐solid types (n = 10), the incidences were 8% and 100%, respectively. These data suggest that MAb 91.9H could be of practical use as a new marker for IM and gastric cancer, and may be valuable for subgrouping poorly differentiated adenocarcinomas. Analyses of the core proteins for 91.9H epitope were then carried out. Comparison of immunostaining of ten poorly differentiated adenocarcinoma cases by MAb MUSE11 against MUC1 gene product with that by MAb 91.9H suggested that 91.9H epitope is not expressed on MUC1. Northern blot analysis of 10 pairs of gastric cancer and adjacent normal tissues with a MUC2 cDNA probe showed that the expression level of MUC2 mRNA was below the limit of detection. Thus, 91.9H epitope may be expressed on other proteins than MUC1 or MUC2 core proteins in gastric cancer.
Close Correlation between the Dephosphorylation of p53 and Growth Suppression by Transforming Growth Factor‐β1 in Nasopharyngeal Carcinoma Cells Transduced with Adenovirus Early Region Genes
Authors: Mogi Yoshihiro , Kato Junji , Horimoto Masayoshi , Takimoto Rishu , Murakami Tsuzuku , Hirayama Atsushi , Kohgo Yutaka , Watanabe Naoki , Niitsu Yoshiro
Published: August 2005

The mechanism of growth inhibition by transforming growth factor (TGF)‐β1 was investigated. We examined the growth inhibitory effects of TGF‐β1 on human nasopharyngeal carcinoma (KB) cells which constitutively expressed p53. TGF‐β1 suppressed the DNA synthesis of KB cells in a dose‐dependent manner. It had minimal effect on adenovirus‐2‐transduced KB cells expressing either adenovirus early region 1B (E1B) or 1A (E1A) product, which respectively binds to p53 or Rb product and inhibits its function, and no growth inhibition at all was observed with KB cells expressing both E1B and E1A products. Dephosphorylation of the p53 was promoted by TGF‐β1 stimulation in KB cells, but not in E1B‐producing KB cells, which sequestrate the function of p53. The growth inhibition of KB cells by TGF‐β1 was significantly reduced by treatment with okadaic acid. These results suggest that p53 transduces the antiproliferative signal of TGF‐β1 possibly through its dephosphorylation.
Binding Sites of Droloxifene in the Cytosol of 7,12‐Dimethylbenz[α]anthracene‐induced Rat Mammary Tumor Cells
Authors: Kawamura Ikuo , Lacey Elizabeth , Tanaka Yoshio , Nishigaki Fusako , Manda Toshitaka , Shimomura Kyoichi
Published: August 2005

The binding sites, other than the estrogen receptor (ER), of the antiestrogens droloxifene (DROL, (E)‐α‐[p[2‐(dimethylamino)ethoxy]‐phenyl]‐α'‐ethyl‐3‐stilbenol) and tamoxifen (TAM), and estradiol‐17β (E2) in the cytosol of 7,12‐dimethylbenz[α]anthracene‐induced rat mammary ER‐positive tumor cells were studied using a high‐performance liquid chromatography (HPLC) gel filtration assay. The cytosol was incubated with 3H‐labeled drug with or without unlabeled drug, and separated by HPLC gel filtration. 3H‐E2 produced two major peaks of radioactivity at fractions No. 40 and No. 70. The peak at fraction No. 70 was identified as the ER in an ER‐enzyme‐immuno assay. This peak was dose‐dependently inhibited by unlabeled DROL or TAM, DROL being a more potent inhibitor than TAM. The peak at fraction No. 40 was also inhibited by co‐incubation with unlabeled DROL or TAM. 3H‐DROL or 3H‐TAM provided only one peak at fraction No. 43. This peak was thought to be an antiestrogen binding site (AEBS), because it was inhibited by unlabeled antiestrogen hut not by E2. The results suggest that the antiestrogens DROL and TAM have a higher affinity for the AEBS than for the ER in the absence of E2, while in the presence of E2 both have an affinity for the ER and inhibit E2 binding to the ER.
Selective Inhibitory Effect of Bufalin on Growth of Human Tumor Cells in vitro: Association with the Induction of Apoptosis in Leukemia HL‐60 Cells
Authors: Jing Yongkui , Ohizumi Hidekazu , Kawazoe Nobuko , Hashimoto Sachiko , Masuda Yutaka , Nakajo Shigeo , Yoshida Takemi , Kuroiwa Yukio , Nakaya Kazuyasu
Published: August 2005

We found that bufalin, an active principle of the Chinese medicine chan'su, has selective inhibitory effects on the growth of various human cancer cells. In order to examine whether the growth‐inhibitory effect of bufalin on human cancer cells is associated with apoptosis, human leukemia cells were treated with bufalin. HL‐60, ML1, and U937 leukemia cells treated with bufalin at 10−8M and above had condensed and fragmented nuclei. Flow cytometric analysis of these cells treated with bufalin showed fragmented DNA smaller than that of the G1 phase. DNA of HL‐60 cells treated with bufalin showed a ladder pattern characteristic of apoptosis, as analyzed by agarose gel electrophoretic analysis. DNA synthesis and topoisomerase II activity of HL‐60 cells were markedly inhibited as the concentration of bufalin was increased. The concentration needed for inducing apoptosis of HL‐60 cells was 10−8M, which is comparable to that of camptothecin, but lower than those of other antitumor drugs such as cisplatin, VP16 and all‐trans retinoic acid. Apoptosis was not observed when human mononuclear and polymorphonuclear cells were treated with 10−6M bufalin for 24 h. These results indicate the association of the growth‐inhibitory effect of bufalin with the induction of apoptosis, at least in HL‐60 cells, and suggest the usefulness of bufalin for differentiation‐apoptosis‐inducing therapy for cancer.
Establishment of a Human Small Cell Lung Cancer Cell Line Producing a Large Amount of Anti‐diuretic Hormone
Authors: Terasaki Takeo , Matsuno Yoshihiro , Shimosato Yukio , Yamaguchi Ken , Ichinose Hiroshi , Nagatsu Toshiharu , Kato Kanefusa
Published: August 2005

A new cancer cell line (Lu‐165) producing a large amount of anti‐diuretic hormone (ADH, 2.8 μg/g protein) was established from a 50‐year‐old small cell lung cancer patient presenting with a syndrome of inappropriate anti‐diuretic hormone secretion. These cells grew well in serum‐supplemented medium and during more than 100 passages they continued producing a large amount of this hormone. This cell line will be a useful tool for studies of the biochemistry and pathology of ADH‐producing cancer.
Dual Function of Macrophage Galactose/N‐Acetylgalactosamine‐specific Lectins: Glycoprotein Uptake and Tumoricidal Cellular Recognition
Authors: Kawakami Kyoko , Yamamoto Kazuo , Toyoshima Satoshi , Osawa Toshiaki , Irimura Tatsuro
Published: August 2005

We investigated whether the interaction of peritoneal macrophages with extracellular ligands is mediated by C‐type lectins specific for galactose and N‐acetylgalactosamine. The carbohydrate‐binding domain of mouse galactose/N‐acetylgalactosamine‐specific lectin was prepared in a recombinant form. The purified recombinant lectins were tested for competitive inhibition against glycoprotein uptake and against tumoricidal effect. Thioglycolate‐elicited macrophages internalized galactosylated bovine serum albumin in vitro. The internalization was blocked by recombinant macrophage lectins. Activated macrophages obtained after intraperitoneal injection of a nonspecific immune potentiator, OK432, did not internalize galactosylated bovine serum albumin. These cells elicited a cytotoxic effect against P815 murine mastocytoma cells, and the effect was blocked by recombinant macrophage lectins. These results indicated that galactose/N‐acetylgalactosamine‐specific C‐type lectins expressed on the surface of inflammatory macrophages and on activated tumoricidal macrophages mediate two distinct functions, i.e. glycoprotein uptake and tumoricidal effector mechanisms.
5′‐Deoxy‐S‐fluorouridine Increases Daunorubicin Uptake in Multidrug‐resistant Cells and Its Activity Is Related with P‐gp 170 Expression
Authors: van der Heyden Sylke , Gheuens Eric , van de Vrie Wim , Van Bockstaele Dirk , Van Oosterom Allan , Eggermont Alexander , De Bruijn Ernst A.
Published: August 2005

Most anticancer agents fail to induce clear responses in the treatment of colorectal cancer. This can be explained by involvement of overexpression of the membrane glycoprotein, P‐gp 170, which is associated with multidrug resistance (MDR), and/or with involvement of ras. Fluoropyrimidines are amongst the few options in the chemotherapeutic treatment of colorectal cancers. 5′‐Deoxy‐5‐fluorouridine (dFUrd) needs intracellular activation via 5‐fluorouracil into 5‐fluoro‐2′‐deoxyuridine‐5′‐monophosphate and 5‐fluorouridine‐S′‐triphosphate. In the present study, the cytotoxic activity of dFUrd in vitro and dFUrd combined with daunorubicin (DNR) was assessed with the (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium) bromide assay in cells with increased P‐gp 170 expression versus controls. Surprisingly, dFUrd was most active in cells with high P‐gp 170 expression, a finding which can not be explained by intracellular metabolic activity only. The results also show that dFUrd improves the DNR uptake in MDR‐positive cells, and this is related with increased cyto‐toxicity of the anthracycline.
Long‐Evans A and C Rat Strains Susceptible to Clastogenic Effects of Chemicals in the Bone Marrow Cells
Authors: Ito Yoshiaki , Fujie Kimiko , Matsuda Shuichi , Takahashi Rei , Maeda Sakan
Published: August 2005

The Clastogenic responses to direct‐ and indirect‐acting carcinogens in bone marrow cells of LEA, LEC, Wistar and SD rats were compared. The frequency of chromosome aberrations (CA) induced by n‐butyl‐N‐nitrosourea or methylmethanesulfonate (MMS), which does not need metabolic activation, was significantly higher in both LEA and LEC rats than in Wistar or SD rats. When bone marrow cells of each rat strain were exposed to MMS in vitro, they also showed the same tendency in CA frequency. Therefore, the high sensitivity of both LEA and LEC rats to the Clastogenic effects of direct‐acting carcinogens seems to result from the sensitivity of the bone marrow cells themselves. On the other hand, the CA frequency induced by 7,12‐dimethylbenz[a]anthracene (DMBA) or aflatoxin bi (AFB1), which requires metabolic activation, was lower in LEC rats than in the other 3 strains. The CA frequency induced by DMBA or AFB1 in LEC rats fed Cu‐free diet since birth (Cu‐free LEC rats) was higher than that in LEC rats given normal diet and lower than that in LEA rats, although the difference was statistically significant only between Cu‐free LEC rats and LEC rats treated with DMBA. The copper concentrations in the livers of LEA, Cu‐free LEC and LEC male rats aged 4 weeks were 5.0 ±0.4, 33 ±7.7 and 106±3.4 μg/g wet weight, respectively. These results suggest that the lower sensitivity of LEC rats to the Clastogenic effects of indirect‐acting carcinogens may be due to the effect of the large amount of copper accumulated in LEC rat liver.
Induction of Tumor Necrosis Factor in Mice by Recombinant Human Macrophage Colony‐stimulating Factor
Authors: Sakurai Takuma , Suzu Shinya , Yamada Muneo , Yanai Nobuya , Kawashima Takuji , Hatake Kiyohiko , Takaku Fumimaro , Motoyoshi Kazuo
Published: August 2005

The effect of recombinant human macrophage colony‐stimulating factor (rhM‐CSF) on endogenous production of tumor necrosis factor (TNF) was investigated in mice. The intravenous injection of lipopolysaccharide (LPS) after the administration of rhM‐CSF via the same route induced the production of endogenous cytotoxic activity in serum as assessed by using TNF‐sensitive miirine L929 cells. The intravenous injection of LPS alone or rhM‐CSF alone did not induce cytotoxic activity. The priming effect of rhM‐CSF was transient and the optimal duration between injections of primer and trigger was 3 h, while the optimal duration between trigger injection and serum sampling was 1 h after LPS injection. Moreover, preinjection of rhM‐CSF enhanced the priming effect of recombinant mouse interferon‐γ. No triggering effect of rhM‐CSF was observed. The cytotoxic activity in the serum was completely neutralized by anti‐mouse TNF‐α polyclonal antibody. These results indicate that rhM‐CSF can be used as a priming agent for endogenous production of TNF in vivo, and raise the possibility of using rhM‐CSF in cancer immunotherapy.
Inhibition of Catabolic Pathway of 5‐Fluorouracil by 3‐Cyano‐2,6‐dihydroxypyridine in Human Lung Cancer Tissues
Authors: Okayasu Takeshi , Sugiyama Kazuhisa , Miyauchi Shun
Published: August 2005

Our studies of the degradation and the phosphorylation of S–fluorouracil (5–FU) in normal and tumor lung tissues from 10 cases of lung cancer have shown that the phosphorylation of 5–FU in the tumor tissues was about 2– to 3–fold higher than that in normal tissues, and that the degradation of 5–FU in tumor tissues was nearly 6–fold higher than that in normal tissues. BOF–A2 is an anti–neoplastic agent newly synthesized from l–ethoxymethyl–5–FU and 3–cyano–2,6–dihydroxypyridine (CNDP). The inhibitory effect of CNDP on the degradation of 5–FU in the tumor tissues was potent (IC50, 3.9 × 10−9M), Thus, BOF–A2 exerts its anti–neoplastic effect on tumors by potentiating the action of 5–FU through inhibition of 5–FU degradation by the CNDP moiety
Morphogenesis of Esophageal Carcinoma Induced by N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine in the House Musk Shrew, Suncus murinus (Insectivora)
Authors: Fujita Yoshiko , Oyaizu Tatsuki , Takahashi Hideki , Oishi Yuji , Tsubura Airo
Published: August 2005

The histological changes occurring in the esophageal mucosa of shrews (Sitncun murinus) after N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) treatment were investigated sequentially. Six‐week‐old female shrews were given a 50 %mUg/ml MNNG solution as drinking water for 30 weeks, and 5 selected at random were killed at 10 and 20 weeks of age, and thereafter at 5‐week intervals until 45 weeks of age. Controls were killed at 45 weeks of age. The MNNG‐induced esophageal lesion in shrews began from hasal cell hyperplasia at 20 weeks of age, followed by dysplasia occurring at 25 weeks of age, then progressed toward intraepithelial carcinoma to invasive squamous cell carcinoma at 35 weeks of age. Apparent sequential dysplasia‐carcinoma transition was seen. Papillomas were seen from 25 weeks of age but there was no evidence of papilloma‐carcinoma sequence. Five MNNG‐untreated shrews killed at the end of the experiment were free of esophageal tumors.