bluuebunny/crossref_metadata_2025 huggingface dataset:
The prognostic significance of p53, p27kip1, p21waf1, HER‐2/neu, and Ki67 proteins expression in gastric cancer: A clinicopathological and immunohistochemical study of 121 Arab patients
Authors: Al‐Moundhri M. S. , Nirmala V. , Al‐Hadabi I. , Al‐Mawaly K. , Burney I. , Al‐Nabhani M. , Thomas V. , Ganguly S. S. , Grant C.
Published: August 2005

Background

The variability of prognosis within a pathological stage of gastric cancer (GC) at presentation, underscores the need for specific biological markers to identify subgroups of patients with aggressive course for intensive treatment. To our knowledge, this is the first study from an Arab population reporting on the relationship of p53, p27kip1, p21waf1, HER‐2/neu, and Ki67 expression, and clinicopathological features and their prognostic significance.

Methods

Formalin‐fixed paraffin‐embedded tumors were studied by immunohistochemistry, using monoclonal antibodies to p53, p27kip1, p21waf1, HER‐2/neu, and Ki67. The results were correlated with clinicopathological features and survival.

Results

M:F = 80:41; median age = 60 years; stage III and IV = 71%; and median follow‐up = 34.4 months. Positive expression rates of p53, p27kip1, p21waf1, Ki67, and HER‐2/neu were 54%, 40%, 8.3%, 70%, and 12% respectively. p53 expression correlated with age <60 years (P = 0.03), tumor size >5cm (P = 0.01), p27kip1 and Ki67 expression (P = 0.0001), and HER‐2/neu (P = 0.04). p21waf1correlated inversely with T‐stage (P = 0.008) and Her‐2/neu expression correlated with histological grade (P = 0.04) and T‐stage (P = 0.008). Univariate analysis showed that p53 overexpression (P = 0.01), fungating and infiltrative macroscopic appearance (P = 0.02), size >5 cm (P = 0.0001), lymph node metastasis (P = 0.0001), p T3 and T4 disease (P = 0.01), and overall stage III and IV (P = 0.0001) disease were adverse prognostic factors. Patients with tumor profiles p53 (−)/p27 (+) had better survival than those with p53 (+)/p27kip1 (−)(P = 0.02). On multivariate analysis by Cox regression model, the expression of p53 (P = 0.03) and lymph node involvement (P = 0.01) were significant adverse prognostic factors for overall survival.

Conclusions

The expression of p53 in Arab patients with GC correlates with aggressive tumor characteristics and is an independent prognostic factor. The combined analysis of p53 and p27kip1 is of added prognostic value. J. Surg. Oncol. 2005;91:243–252. © 2005 Wiley‐Liss, Inc.
Evaluation of the sensitivity of miniaturized liquid chromatography‐electrospray ionization‐mass spectrometry for pharmaceutical analysis
Authors: Kranendijk Martijn , Waterval Joop C. M. , Somsen Govert W. , de Jong Gerhardus J.
Published: August 2005

LC‐ESI‐MS is applied frequently in pharmaceutical analysis. The sample amount is generally not restricted, however with LC‐ESI‐MS, a lack of sensitivity may still be observed with standard‐bore LC columns in isocratic mode. Therefore, it was investigated whether increased sensitivity could be achieved by using miniaturized LC‐ESI‐MS. Seven columns ranging from 0.1 to 4.6 mm ID were tested using several instrument setups. For proper comparison, a sensitivity gain factor (SGF) was introduced. The SGF expresses the extra sensitivity that may be obtained on top of the normal increase of peak concentration, which can be expected when the column ID is reduced. Desogestrel, mirtazapine, and sugammadex sodium were used as test compounds. For desogestrel and sugammadex sodium, the SGF increased up to a factor of 5–13 when the column ID was reduced, indicating enhanced ionization efficiencies at lower flow rates. Optimum sensitivity was found for the 0.3 mm column coupled in combination with a microinjection valve and a dedicated low flow rate interface. For mirtazapine, no increase of SGF was observed when the column ID was decreased. Apparently, the ionization efficiency of this compound is not affected by the flow rate and the spray quality.
Stimulated Raman scattering in mid IR spectral range
2.31–2.75–3.7 μm in
BaWO4 crystal under 1.9 and
1.56 μm pumping
Authors: Basiev T T , Basieva M N , Doroshenko M E , Fedorov V V , Osiko V V , Mirov S B
Published: August 2005

Stimulated Raman scattering (SRS) in newly developed
BaWO4 crystal was investigated. Under 1.9 μm pumping one
Stokes component and under 1.56 μm pumping several (up to
four) Stokes components were observed. SRS and laser breakdown
thresholds were measured. For the first time 2.75 μm and
3.7 μm radiation was obtained using crystalline Raman shifter.
Stability of transonic shocks for the full Euler system in supersonic flow past a wedge
Authors: Fang Beixiang
Published: August 2005

We study the stability of transonic shocks in steady supersonic flow past a wedge. It is known that in generic case such a problem admits two possible locations of the shock front, connecting the flow ahead of it and behind it. They can be distinguished as supersonic–supersonic shock and supersonic–subsonic shock (or transonic shock). Both these possible shocks satisfy the Rankine–Hugoniot conditions and the entropy condition. We prove that the transonic shock is conditionally stable under perturbation of the upstream flow or perturbation of wedge boundary. Copyright © 2005 John Wiley & Sons, Ltd.
Cooperative effects in hydrogen‐bonding of protein secondary structure elements: A systematic analysis of crystal data using Secbase
Authors: Koch O. , Bocola M. , Klebe G.
Published: August 2005

A systematic analysis of the hydrogen‐bonding geometry in helices and β sheets has been performed. The distances and angles between the backbone carbonyl O and amide N atoms were correlated considering more than 1500 protein chains in crystal structures determined to a resolution better than 1.5 Å. They reveal statistically significant trends in the H‐bond geometry across the different secondary structural elements. The analysis has been performed using Secbase, a modular extension of Relibase (Receptor Ligand Database) which integrates information about secondary structural elements assigned to individual protein structures with the various search facilities implemented into Relibase. A comparison of the mean hydrogen‐bond distances in α helices and 310 helices of increasing length shows opposing trends. Whereas in α helices the mean H‐bond distance shrinks with increasing helix length and turn number, the corresponding mean dimension in 310 helices expands in a comparable series. Comparing similarly the hydrogen‐bond lengths in β sheets there is no difference to be found between the mean H‐bond length in antiparallel and parallel β sheets along the strand direction. In contrast, an interesting systematic trend appears to be given for the hydrogen bonds perpendicular to the strands bridging across an extended sheet. With increasing number of accumulated strands, which results in a growing number of back‐to‐back piling hydrogen bonds across the strands, a slight decrease of the mean H‐bond distance is apparent in parallel β sheets whereas such trends are obviously not given in antiparallel β sheets. This observation suggests that cooperative effects mutually polarizing spatially well‐aligned hydrogen bonds are present either in α helices and parallel β sheets whereas such influences seem to be lacking in 310 helices and antiparallel β sheets. Proteins 2005. © 2005 Wiley‐Liss, Inc.
Incorporating time‐dependent covariates in survival analysis using the LVAR method
Authors: Liu Yali , Craig Bruce A.
Published: August 2005

In survival analysis, use of the Cox proportional hazards model requires knowledge of all covariates under consideration at every failure time. Since failure times rarely coincide with observation times, time‐dependent covariates (covariates that vary over time) need to be inferred from the observed values. In this paper, we introduce the last value auto‐regressed (LVAR) estimation method and compare it to several other established estimation approaches via a simulation study. The comparison shows that under several time‐dependent covariate processes this method results in a smaller mean square error when considering the time‐dependent covariate effect. Copyright © 2005 John Wiley & Sons, Ltd.
The role of religion in the Dutch fertility transition: starting, spacing, and stopping in the heart of the Netherlands, 1845–1945
Authors: BAVEL JAN VAN , KOK JAN
Published: August 2005

This contribution investigates how religion retarded the Dutch fertility transition by looking at how denominations were associated with the timing of first births (starting), the length of birth intervals (spacing), and the timing of last births (stopping). First, we apply a simple descriptive model of starting, spacing, and stopping to life-course data from the province of Utrecht. Then, we apply multivariate regression to assess the independent effects of religious denominations, net of socio-economic status, on stopping behaviour. The results indicate that liberal Protestants were more prone to adopt stopping behaviour than orthodox Protestants and Catholics.
Adenosine A1 Receptor Knockout Mice Develop Lethal Status Epilepticus after Experimental Traumatic Brain Injury
Authors: Kochanek Patrick M , Vagni Vincent A , Janesko Keri L , Washington Christopher B , Crumrine Patricia K , Garman Robert H , Jenkins Larry W , Clark Robert SB , Homanics Gregg E , Dixon C Edward , Schnermann Jurgen , Jackson Edwin K
Published: August 2005

Adenosine, acting at A1 receptors, exhibits anticonvulsant effects in experimental epilepsy—and inhibits progression to status epilepticus (SE). Seizures after traumatic brain injury (TBI) may contribute to pathophysiology. Thus, we hypothesized that endogenous adenosine, acting via A1 receptors, mediates antiepileptic benefit after experimental TBI. We subjected A1-receptor knockout (ko) mice, heterozygotes, and wild-type (wt) littermates ( n = 115) to controlled cortical impact (CCI). We used four outcome protocols in male mice: (1) observation for seizures, SE, and mortality in the initial 2 h, (2) assessment of seizure score (electroencephalogram (EEG)) in the initial 2 h, (3) assessment of mortality at 24 h across injury levels, and (4) serial assessment of arterial blood pressure, heart rate, blood gases, and hematocrit. Lastly, to assess the influence of gender on this observation, we observed female mice for seizures, SE, and mortality in the initial 2 h. Seizure activity was noted in 83% of male ko mice in the initial 2 h, but was seen in no heterozygotes and only 33% of wt ( P < 0.05). Seizures in wt were brief (1 to 2 secs). In contrast, SE involving lethal sustained (>1 h) tonic clonic activity was uniquely seen in ko mice after CCI (50% incidence in males), ( P < 0.05). Seizure score was twofold higher in ko mice after CCI versus either heterozygote or wt ( P < 0.05). An injury-intensity dose–response for 24 h mortality was seen in ko mice ( P < 0.05). Physiologic parameters were similar between genotypes. Seizures were seen in 100% of female ko mice after CCI versus 14% of heterozygotes and 25% wt ( P < 0.05) and SE was restricted to the ko mice (83% incidence). Our data suggest a critical endogenous anticonvulsant action of adenosine at A1 receptors early after experimental TBI.
Effect of ischaemic preconditioning on regional release of inflammatory markers
Authors: Lee Tsung-Ming , Lin Mei-Shu , Tsai Chang-Her , Chang Nen-Chung
Published: August 2005

Systemic markers of inflammation may be increased in patients after percutaneous coronary intervention. In the present study, we evaluated whether IP (ischaemic preconditioning) attenuated inflammation by activating KATP (ATP-sensitive potassium) channels in patients undergoing coronary angioplasty. Patients (n=36) undergoing angioplasty of a major left coronary artery were allocated randomly to one of four groups: a control group, a group receiving nicorandil (an agonist of KATP channels), an IP group or an IP group pretreated with glibenclamide (an antagonist of KATP channels). To measure the release of sCD40L, P-selectin and myeloperoxidase from the ischaemic region, blood samples were drawn simultaneously from the ascending aorta and the great cardiac vein before and 15 min after coronary angioplasty. At 15 min after angioplasty, a significant increase in sCD40L and P-selectin levels in the great cardiac vein in the control group was observed. IP- and nicorandil-treated patients did not show a significant change in sCD40L and P-selectin levels in response to angioplasty. However, the IP-induced attenuation of sCD40L and P-selectin release was abolished by administering glibenclamide. The change in myeloperoxidase levels mirrored those of sCD40L and P-selectin. The levels of inflammatory markers in the aorta remained stable throughout the study. Patients undergoing angioplasty had increased sCD40L and P-selectin levels in the ischaemic region. In conclusion, IP abolished angioplasty-induced myeloperoxidase release by preventing activated platelet-induced P-selectin release via a KATP-channel-initiated pathway. Therefore, in addition to its primary effect on cardioprotection, IP may also provide beneficial anti-inflammatory effects on the interaction between platelets and neutrophils.
NADPH oxidase and endothelial cell function
Authors: Ray Robin , Shah Ajay M.
Published: August 2005

Intracellular ROS (reactive oxygen species) such as superoxide and H2O2 have been increasingly appreciated to have a role in endothelial pathophysiology. Of the several sources within the vasculature, a family of multi-subunit NADPH oxidases appears to be a predominant contributor of endothelial superoxide. More importantly, this enzyme system is activated by numerous stimuli and is involved in triggering diverse intracellular signalling pathways (‘redox-sensitive’ signalling pathways) that have a central role in conditions such as endothelial activation and inflammation, cell growth, apoptosis and hypertrophy. Furthermore, NADPH oxidase-derived superoxide contributes to the impairment of endothelium-dependent vasodilatation by inactivating nitric oxide; the resultant endothelial dysfunction is implicated in the pathophysiology of diseases such as atherosclerosis, hypertension, diabetic vasculopathy and heart failure. A detailed understanding of the regulation of NADPH oxidases and their modulation and downstream effects may define novel therapeutic targets for cardiovascular disease prevention and treatment in the clinical setting, in contrast with global antioxidant therapy which has to date been disappointing.
Tracing the minimum-energy path on the free-energy surface
Authors: Fleurat-Lessard Paul , Ziegler Tom
Published: August 2005

The free-energy profile of a reaction can be estimated in a molecular-dynamics approach by imposing a mechanical constraint along a reaction coordinate (RC). Many recent studies have shown that the temperature can greatly influence the path followed by the reactants. Here, we propose a practical way to construct the minimum-energy path directly on the free-energy surface at a given temperature. First, we follow the blue-moon ensemble method to derive the expression of the free-energy gradient for a given RC. These derivatives are then used to find the actual minimum-energy reaction path at finite temperature, in a way similar to the intrinsic reaction path of Fukui on the potential-energy surface. [K. Fukui, J. Phys. Chem. 74, 4161 (1970)]. Once the path is known, one can calculate the free-energy profile using thermodynamic integration. We also show that the mass-metric correction cancels for many types of constraints, making the procedure easy to use. Finally, the minimum-free-energy path at 300K for the addition of CCl2 to ethylene is compared with a path based on a simple one-dimensional reaction coordinate. A comparison is also given with the reaction path at 0K.
Phase-field modeling of stress-induced surface instabilities in heteroepitaxial thin films
Authors: Seol D. J. , Hu S. Y. , Liu Z. K. , Chen L. Q. , Kim S. G. , Oh K. H.
Published: August 2005

A phase-field model for investigating the surface morphological evolution of a film is developed, taking into account the surface energies of film and substrate, the interfacial energy between the film and substrate, and the elastic energy associated with the lattice mismatch between the film and substrate. Using the lattice mismatch and the surface energies for the Ge∕Si heteroepitaxial system, the morphology of islands and the formation of a wetting layer are investigated using two-dimensional simulations. The results show that the wetting angle increases continuously with the increase in the lattice mismatch, and the surface angle of the island on wetting layer varies with the island size. It is demonstrated that the anisotropy of elastic interactions alone is not sufficient to cause surface angle discontinuity or faceting that is observed in experiments.
Carrier compensation near tail region in aluminum- or boron-implanted 4H–SiC (0001)
Authors: Negoro Y. , Kimoto T. , Matsunami H.
Published: August 2005

Electrical behavior of implanted Al and B near implant-tail region in 4H–SiC (0001) after high-temperature annealing has been investigated. Depth profiles of Al and B acceptors determined by capacitance-voltage characteristics are compared with those of Al and B atoms measured by secondary-ion-mass spectrometry. For Al+ (aluminum-ion) implantation, slight in-diffusion of Al implants occurred in the initial stage of annealing at 1700°C. The profile of the Al-acceptor concentration in a “box-profile” region as well as an “implant-tail” region is in good agreement with that of the Al-atom concentration, indicating that nearly all of the implanted Al atoms, including the in-diffused Al atoms, work as Al acceptors. Several electrically deep centers were formed by Al+ implantation. For B+ (boron-ion) implantation, significant out- and in-diffusion of B implants occurred in the initial stage of annealing at 1700°C. A high density of B-related D centers exists near the tail region. In the tail region, the sum of B-acceptor concentration and D-center concentration corresponds to the B-atom concentration. C+ (carbon-ion) coimplantation with a ten times higher dose than B+ effectively suppressed the B diffusion, but additional deep centers were introduced by C+ coimplantation.
Combinatorial screening of ternary NiO–Mn2O3–CuO composition spreads
Authors: Kukuruznyak D. A. , Ahmet P. , Chikyow T. , Yamamoto A. , Ohuchi F. S.
Published: August 2005

We describe the screening of large combinatorial oxide libraries for their electric transport characteristics. Complete ternary composition spreads of NiO–Mn2O3–CuO oxide alloys were deposited onto conducting Nb-doped SrTiO3 substrates using the combinatorial pulsed laser deposition technique. Resistance-temperature relations for each composition in the spread were determined using a custom-designed scanning probe. Ternary and binary electrically conducting alloys are located around Ni0.45Cu0.75Mn1.65O4 (the lowest resistance point) and CuMn2O4 compositions, respectively. The temperature sensitivities of the compositions Ni0.3Cu0.3Mn2.4O4,Cu0.84Mn2.16O4, and Cu1.35Mn1.65O4 were 5.0%/°C, 3.5%/°C, and 3.0%/°C, respectively. From this screening we propose compounds for thin-film negative temperature coefficient thermistors with standardized characteristics.
Zinc oxide nanoarrays in nanoporous nickel phosphate with a huge blueshift ultraviolet-visible exciton absorption peak
Authors: Chen Zhi , Gao Qiuming , Ruan Meiling , Shi Jianlin
Published: August 2005

Zinc oxide (ZnO) nanoarray prepared in the template of nanoporous nickel(II) phosphate Versailles Santa Barbara-1 (VSB-1) crystal exhibits an unusual ultraviolet-visible exciton absorption peak and an absorption shoulder. The exciton absorption peak at 266nm with the largest blueshift of 122nm up to now and narrow absorption peak with a full width at half maximum (FWHM) of about 34nm and the narrow photoluminescence emission peak 380nm with a FWHM of about 30nm, compared with that of bulk ZnO, are due to the quantum-confinement effects and the narrow size distribution of ZnO in the pores of VSB-1. This material presents potential applications in the theoretical research and fabrication of future quantum devices.
Generation of frequency-tunable nanoacoustic waves by optical coherent control
Authors: Yu Cheng-Ta , Lin Kung-Hsuan , Hsieh Chia-Lung , Pan Chang-Chi , Chyi Jen-Inn , Sun Chi-Kuang
Published: August 2005

We have developed a system to generate arbitrary wave-form nanoacoustic waves (NAWs) with a piezoelectric InGaN∕GaN single-quantum well. Based on an optical coherent control technique, acoustic frequency tunability in the subterahertz range is realized within only one fixed sample. The acoustic generation mechanisms, especially the in-well piezoelectric field Coulomb screening which tends to be saturated at high carrier concentrations, are discussed with optical power dependency. With the generated NAWs propagating in the c axis of a GaN thin film, the lifetime of the 500 GHz longitudinal-acoustic phonon pulses in GaN is measured to be longer than 420 ps, corresponding to a GaN depth more than 3.3μm.
Polarization-independent and fast-response phase modulation using a normal-mode polymer-stabilized cholesteric texture
Authors: Lin Yi-Hsin , Ren Hongwen , Fan Yun-Hsing , Wu Yung-Hsun , Wu Shin-Tson
Published: August 2005

Fast-response, polarization-independent, and hysteresis-free phase-only modulation using a normal-mode polymer-stabilized cholesteric texture (PSCT) is demonstrated. Although the remaining phase change in the high-voltage regime is small, it is still useful for making microdevices. Polarization-independent tunable-focus microlens arrays using such a PSCT are demonstrated.
Optical diffraction of second-harmonic signals in the LiBO2-Nb2O5 glasses induced by self-organized LiNbO3 crystallites
Authors: Venkataraman B. Harihara , Prasad N. Syam , Varma K. B. R. , Rodriguez Vincent , Maglione Mario , Vondermuhll R. , Etourneau J.
Published: August 2005

The nanocrystallites (≈3nm) of LiNbO3, evolved in the (100−x)LiBO2-xNb2O5 (5⩽x⩽20, in molar ratio) glass system exhibited intense second-harmonic signals in transmission mode when exposed to infrared (IR) light at λ=1064nm. The second-harmonic waves were found to undergo optical diffraction which was attributed to the presence of self-organized submicrometer-sized LiNbO3 crystallites that were grown within the glass matrix along the parallel damage fringes created by the IR laser radiation. Micro-Raman studies carried out on the laser-irradiated samples confirmed the self-organized crystallites to be LiNbO3.
High-quality thin single-crystal γ-Al2O3 films grown on Si (111)
Authors: Wu S. Y. , Hong M. , Kortan A. R. , Kwo J. , Mannaerts J. P. , Lee W. C. , Huang Y. L.
Published: August 2005

Single-crystal Al2O3 films have been epitaxially grown on Si (111) substrates despite a lattice mismatch of more than 30%. The oxide was electron-beam evaporated from a high-purity sapphire source. The structural and morphological studies carried out by x-ray diffraction, x-ray reflectivity, atomic force microscopy, and transmission electron microscopy, with the initial epitaxial growth observed by in situ reflection high-energy electron diffraction show that the oxide films as thin as 3.8 nm have the cubic γ-phase with a very uniform thickness and a high structural perfection. The film surface is very smooth with a roughness of 0.12 nm and the oxide∕Si interface is atomically sharp. The γ-Al2O3 films are well aligned with Si substrate with an orientation relationship of Si(111)∕∕Al2O3(222), Si[220]∕∕Al2O3[440].
InGaAsN
∕
GaAs
quantum-well lasers using two-step and nitride passivation growth
Authors: Chiu Pei-Chin , Yeh Nien-Tze , Hong Chao-Chi , Hsieh Tung Po , Tsai Yao-Tsong , Ho Wen-Jeng , Chyi Jen-Inn
Published: August 2005

The optical properties of InGaAsN QW grown on AlGaAs∕GaAs cladding layers were investigated. Al contamination in the quantum well due to the memory effect is responsible for the degradation of optical quality. We propose a growth method to reduce the Al contamination by growth interruption and dimethylhydrazine passivation. This approach improves the optical properties as well as simplifies the growth processes significantly as compared to the reported methods.
Bound-to-bound midinfrared intersubband absorption in carbon-doped GaAs∕AlGaAs quantum wells
Authors: Malis Oana , Pfeiffer Loren N. , West Kenneth W. , Sergent A. Michael , Gmachl Claire
Published: August 2005

Bound-to-bound intersubband absorption in the valence band of modulation-doped GaAs quantum wells with digitally alloyed AlGaAs barriers was studied in the midinfrared wavelength range. A high-purity solid carbon source was used for the p-type doping. Strong narrow absorption peaks due to heavy-to-heavy hole transitions are observed with out-of-plane polarized light, and weaker broader features with in-plane polarized light. The heavy-to-heavy hole transition energy spans the spectral range between 206 to 126 meV as the quantum well width is increased from 25 to 45 Å. The experimental results are found to be in agreement with calculations of a six-band k∙p model taking into account the full band structure of the digital alloy.
Redundancy, Readjustment, and Employability: What Can We Learn from the 2000 Harland & Wolff Redundancy?
Authors: Shuttleworth Ian , Tyler Peter , McKinstry Darren
Published: August 2005

Large-scale redundancies have been a common feature of the UK industrial landscape in recent years and a changing labour market and institutional context supports the need for ongoing research into this important area. In this paper the authors examine the postredundancy experience of workers who were made redundant from Harland & Wolff in Belfast in 2000 to identify the factors that affected the employability of those workers and to consider some aspects of state intervention. These workers might be regarded as being potentially disadvantaged with high risks of long-term unemployment and so provide a stiff test for policies for successful postredundancy transitions into the new economy with its demands for employability and flexibility. Employability is usually associated with supply-side measures, but the role of labour demand also needs to be explored, and the adjustment process is thus considered against the background of overall labour-market change that has occurred in Northern Ireland in recent years. The authors suggest that state intervention through the provision of job-related training can be a successful response to redundancy but that general skills training is questionable because of low uptake and perceptions of irrelevance. Job-specific training was not sufficient on its own to explain the relatively high rates of reemployment in this case. The presence of a group of engineering employers provided both the conditions for job-related training and then the vacancies for the redundant workers to fill. In debates about employability it is important that the demand-side of the labour market should receive sufficient attention. The authors also suggest that there are wider merits in taking a geographical approach to labour-market policy even if only restricted to the supply side. They suggest that employability should be developed in ways specific to local conditions and groups of workers. The differences in the characteristics of the workers who followed different postredundancy paths led to the conclusion that interventions could be precisely targeted to clearly defined groups of workers.
Stearoyl-CoA desaturase-2 gene expression is required for lipid synthesis during early skin and liver development
Authors: Miyazaki Makoto , Dobrzyn Agnieszka , Elias Peter M. , Ntambi James M.
Published: August 2005

There are four known stearoyl-CoA desaturase (SCD) enzyme isoforms in mouse and two in humans that are required for the biosynthesis of monounsaturated fatty acids, mainly oleate. SCD1 isoform plays a role in the regulation of energy metabolism and lipid synthesis, but the roles of the other SCD isoforms have not been investigated. Here we show that the SCD2 isoform is important in lipid synthesis in early development and is required for survival. SCD2-deficient (
Scd2
-/-
) neonatal mice have a skin permeability barrier defect and a specific repartitioning of linoleic acid from epidermal acylceramide species into phospholipids.
SCD2
expression is high in liver of wild-type mouse embryos and neonates between embryonic day 18.5 and 21 days of age and is decreased in adult mice.
SCD1
expression, on the other hand, is induced after weaning. The liver, skin, and plasma triglyceride contents are decreased in the neonates but are not altered in the adult
Scd2
-/-
mice. These results indicate that, although SCD1 expression is important in adult mice, SCD2 is crucial in the synthesis of monounsaturated fatty acids that are required for maintaining normal epidermal permeability barrier function and biosynthesis of lipids during early skin and liver development.
Effects of the tumor inhibitory triterpenoid avicin G on cell integrity, cytokinesis, and protein ubiquitination in fission yeast
Authors: Gutterman Jordan U. , Lai Hong T. , Yang Peirong , Haridas Valsala , Gaikwad Amos , Marcus Stevan
Published: August 2005

Avicins comprise a class of triterpenoid compounds that exhibit tumor inhibitory activity. Here we show that avicin G is inhibitory to growth of the fission yeastSchizosaccharomyces pombe.S. pombecells treated with a lethal concentration of avicin G (20 μM) exhibited a shrunken morphology, indicating that avicin G adversely affects cell integrity. Cells treated with a sublethal concentration of avicin G (6.5 μM) exhibited a strong cytokinesis-defective phenotype (multiseptated cells), as well as cell morphology defects. These phenotypes bear resemblance to those resulting from loss of Rho1 GTPase function inS. pombe. Indeed, Rho1-deficientS. pombecells were strongly hypersensitive to avicin G, suggesting that the compound may perturb Rho1-dependent processes. Consistent with previously observed effects in human Jurkat T cells, avicin G treatment resulted in hyperaccumulation of ubiquitinated proteins inS. pombecells. Interestingly, proteasome-defectiveS. pombemutants were not markedly hypersensitive to avicin G, whereas an anaphase-promoting complex (mitotic ubiquitin ligase) mutant exhibited avicin G resistance, suggesting that the increase in levels of ubiquitinated proteins resulting from avicin G treatment may be due to increased protein ubiquitination, rather than inhibition of 26S proteasome activity. Mutants defective in the cAMP/PKA pathway also exhibited resistance to avicin G. Our results suggest thatS. pombewill be a useful model organism for elucidating molecular targets of avicin G and serve as a guide to clinical application where dysfunctional aspects of Rho and/or ubiquitination function have been demonstrated as in cancer, fibrosis, and inflammation.
Deubiquitinating function of ataxin-3: Insights from the solution structure of the Josephin domain
Authors: Mao Yuxin , Senic-Matuglia Francesca , Di Fiore Pier Paolo , Polo Simona , Hodsdon Michael E. , De Camilli Pietro
Published: August 2005

Spinocerebellar ataxia type 3 is a human neurodegenerative disease resulting from polyglutamine tract expansion. The affected protein, ataxin-3, which contains an N-terminal Josephin domain followed by tandem ubiquitin (Ub)-interacting motifs (UIMs) and a polyglutamine stretch, has been implicated in the function of the Ub proteasome system. NMR-based structural analysis has now revealed that the Josephin domain binds Ub and has a papain-like fold that is reminiscent of that of other deubiquitinases, despite primary sequence divergence but consistent with its deubiqutinating activity. Mutation of the catalytic Cys enhances the stability of a complex between ataxin-3 and polyubiquitinated proteins. This effect depends on the integrity of the UIM region, suggesting that the UIMs are bound to the substrate polyubiquitin during catalysis. We propose that ataxin-3 functions as a polyubiquitin chain-editing enzyme.
Pollution related effects on immune function and stress in a free‐living population of pied flycatcher Ficedula hypoleuca
Authors: Eeva Tapio , Hasselquist Dennis , Langefors Åsa , Tummeleht Lea , Nikinmaa Mikko , Ilmonen Petteri
Published: August 2005

We investigated whether exposure to heavy metal pollution affected the immune function of individuals in a free living population of a small insectivorous passerine bird, the pied flycatcher Ficedula hypoleuca. We measured humoral immune responses in two study areas: a polluted area in the vicinity of a copper smelter and a control area far from the smelter. Plasma corticosterone level and blood heterophil/lymphocyte ratio (H/L) were used as more general physiological measures of stress. The immune response of F. hypoleuca was not suppressed by pollution stress. In contrast, we found that F. hypoleuca males showed stronger humoral immune responses to a novel antigen (tetanus toxoid) in the polluted environment than in the unpolluted one. After the immunization of males, numbers of lymphocytes rose significantly more in the polluted area, leading to a smaller H/L ratio than in males from the control area. Females showed no pollution related effects on their immune responses. Corticosterone levels of males and nestlings were not related to pollution levels. Nestlings showed somewhat higher H/L ratios and lower fledging success in the polluted area, both factors indicating increased stress levels in a polluted area. Our results suggest that humoral immune response of male F. hypoleuca may be enhanced under moderate levels of heavy metal pollution. Enhanced immune function may, however, also be costly for birds and the higher humoral immune responses in polluted areas may thus have negative effects on the birds’ breeding performance and survival.
Immunosuppressive Effect of Shedding Intercellular Adhesion Molecule 1 Antigen on Cell‐mediated Cytotoxicity against Tumor Cells
Authors: Koyama Shohei
Published: August 2005

We have examined whether shedding intercellular adhesion molecule‐1 (ICAM‐1) antigen from cultured tumors is able to inhibit the leukocyte function‐associated antigen‐1 (LFA‐1)/ICAM‐1 interaction between cytotoxic effector cells and ICAM‐1+ target tumor cells. The cytotoxic activity of lymphokine‐activated killer (LAK) cells incubated with spent media from ICAM‐1+ tumor cells, especially interferon‐γ‐stimulated tumor cells, was significantly decreased as compared with that of LAK cells treated with fresh culture medium without ICAM‐1 antigen. Treatment of LAK cells with spent media from ICAM‐1− tumor cells did not cause a significant decrease of the cytolytic activity towards ICAM‐1+ tumor cells. These findings suggest that shedding of ICAM‐1 antigen could be involved in binding of LFA‐1 to LAK cells, resulting in reduced cytolytic activity.
Presence of p53 Mutations in 3Y1‐B Clone 1‐6: A Rat Cell Line Widely Used as a Normal Immortalized Fibroblast
Authors: Ushijima Toshikazu , Makino Hiroshi , Nakayasu Michie , Aonuma Shizu , Takeuchi Masaki , Segawa Kaoru , Sugimura Takashi , Nagao Minako
Published: August 2005

The 3Y1 cell line, established from a rat whole embryo, is widely used as a normal immortalized fibroblast. We analyzed p53 mutations in four clonal lines derived from the 3Y1 cell line; 3Y1‐B clone 1–6, 3Y1‐C and two clonal lines (3Y1 cl‐3 and 3Y1 cl‐6) which had been transformed by the human papilloma virus E6 gene. Polymerase chain reaction (PCR)‐single strand conformation polymorphism (SSCP) analysis and DNA sequencing showed that three clonal lines had a double mutation at codons 130 and 136 on the same allele and that the other clonal line, 3Y1 cl‐3, had no mutations. 3Y1‐B clone 1–6, which has been registered as the standard clonal line at the Japanese Cancer Research Resources Bank, demonstrated weak bands of the wild type allele, suggesting the existence of heterogeneous cell types in this “clonal” line. PCR‐SSCP analysis of 25 subclones obtained by limiting dilution of 3Y1‐B clone 1–6 cells revealed a mixture of two types of cells; 12 subclones showed only the bands of mutated allele, and 13 subclones showed both bands of the wild and mutated p53 alleles. These findings should be taken into consideration when using this cell line as a normal immortalized cell line.
Diet, Serum Markers and Breast Cancer Mortality in China
Authors: Guo Wan‐De , Chow Wong‐Ho , Zheng Wei , Li Jun‐Yao , Blot William J.
Published: August 2005

This county‐based correlation study examined associations of breast cancer mortality with dietary habits and certain serum biochemical markers, utilizing data collected from an ecological survey in 65 Chinese rural counties. Univariate correlation and multivariate regression analysis showed that consumption of animal foods, including eggs, fish and meat, was positively linked to county‐wide mortality rates of breast cancer in Chinese women. No clear associations between breast cancer mortality rates and consumption of green vegetables, carrots and fruits were observed in this study. A modest inverse correlation between serum vitamin C levels and breast cancer mortality was observed, while selenium levels were positively related to the mortality rates. Positive correlations for serum ferritin and hemoglobin were found, in agreement with recent reports of an elevated cancer risk with increased body iron stores. Limitations of these ecological data preclude causal inferences, but the findings provide clues to breast cancer risk and protective factors in a low incidence area of the world.
Increased Rate of Spontaneous Mitotic Recombination in T Lymphocytes from a Bloom's Syndrome Patient Using a Flow‐cytometric Assay atHLA‐ALocus
Authors: Kusunoki Yoichiro , Hayashi Tomonori , Hirai Yuko , Kushiro Jun‐ichi , Tatsumi Kouichi , Kurihara Takayuki , Zghal Mohamed , Kamoun Mohamed R. , Takebe Hiraku , Jeffreys Alec , Nakamura Nori , Akiyama Mitoshi
Published: August 2005

Bloom's syndrome (BS) is an autosomal recessive disorder conferring high propensity for cancer and displaying a high degree of genetic instability; the frequency of sister chromatid exchange is characteristically 10 times above background. The symmetrical four‐armed chromatid interchanges are much more readily detected in peripheral blood lymphocytes of BS patients, suggesting that the frequency of somatic recombination is also increased. In the present study, the rate of spontaneous loss ofHLA‐Aallele expression was estimated following fluctuation analysis in cultured T lymphocytes using a flow‐cytometric assay. It was found to be 10 times or more higher than normal in lymphocytes from a BS patient. Molecular and chromosome analyses showed that all 13 independent variants from the patient were most likely derived from somatic recombinations. Further tests for loss of heterozygosity at a closely linked proximal locus,HLA‐DQA1, showed that as many as half of the recombinants retained heterozygosity irrespective of the donor. The results suggest that the HLA region is hyperrecombinogenic in somatic cells and that the elevated recombination rate in BS cells results from the general increase at ordinary sites and not from random creation of unusual sites for recombination.
Chemotherapy Targeting Regional Lymph Nodes by Gastric Submucosal Injection of Liposomal Adriamycin in Patients with Gastric Carcinoma
Authors: Akamo Yoshimi , Mizuno Isamu , Yotsuyanagi Toshihisa , Ichino Tatsuo , Tanimoto Noritaka , Yamamoto Tetsuya , Nagata Mariko , Takeyama Hiromitsu , Shinagawa Nagao , Yura Jiro , Manabe Tadao
Published: August 2005

We investigated the delivery of adriamycin (ADR) to the regional lymph nodes of the stomach following the gastric submucosal injection of liposomal adriamycin (Lipo‐ADR) in 34 gastric carcinoma patients, as well as following intravenous administration of free ADR (F‐ADR) in another 18 patients. Prior to radical gastrectomy, Lipo‐ADR was endoscopically injected into the gastric submucosa adjacent to the primary tumor via a needle‐tipped catheter. After Lipo‐ADR injection, the ADR concentration in the primary and secondary drainage lymph nodes was higher than in the other regional lymph nodes. Thus, the regional nodes more susceptible to metastasis showed higher levels of ADR. In contrast, the intravenous administration of F‐ADR produced a similar and far lower ADR concentration in all the nodes. Delivery of ADR to the primary drainage lymph nodes following injection of 5 ml of Lipo‐ADR was compared with delivery to the left gastric artery lymph nodes after intravenous administration of an equal dose of F‐ADR. The ADR levels (μg/g) after gastric submucosal injection were 15.1±8.30 on day 1 (n = 4); and 11.9±4.80 on day 4 (n = 6). Those after intravenous administration were 0.29±0.10 on day 1 (n = 4); and 0.36±0.0 on day 4 (n = 2). The differences between the two groups were significant (P<0.05). The ADR levels after the gastric submucosal injection were far higher than those after intravenous administration. These findings indicate that the gastric submucosal injection of Lipo‐ADR can specifically deliver ADR to the regional lymph nodes at high concentrations. Such preoperative adjuvant chemotherapy targeting the regional lymph nodes may be useful for preventing the lymph node recurrence of gastric carcinoma.
Enhancement of Tumor Proliferation by Cyclosporine A in Early Phase of Experimental Hepatic Metastasis
Authors: Yokoyama Itsuo , Hayashi Shuji , Sato Eisaku , Kobayashi Takaaki , Negita Masataka , Uchida Kazuharu , Takagi Hiroshi
Published: August 2005

The effect of cyclosporine A (CsA) on in vivo growth of hepatic metastasis was studied. Murine colon 38 tumor cells (1 × 105) were inoculated via the superior mesenteric vein. Mice were grouped depending on CsA dosage and time schedules: Group A: CsA 30 mg/kg body weight on the 7, 8 and 9th post tumor inoculation days hy gavage; Group B: CsA 15 mg/kg body weight 30 min before tumor inoculation and 2 times more at 24 h intervals; Group C: CsA 30 mg/kg body weight at the same dose timing as Group B. Measurement of the diameter of the largest tumor serially by weekly laparotomy up to 4 weeks revealed that the tumor growth rates were significantly greater in Groups B and C than those in Group A or the control (without CsA). The mean tumor doubling times in the control, and Groups A, B and C were 2.2±1.3, 2.0±0.5, 1.5±0.4 and 1.3±0.8 days, respectively. The mean tumor numbers of hepatic metastasis were 13.2±8.3, 11.3±7.3, 19.4±8.7 and 19.6±6.8, respectively. Values of tumor proliferation index obtained by bromodeoxyuridine immunohistochemistry were 10.0±6.1%, 14.9±8.0%, 28.6±8.2% and 30.1±12.4%, respectively, with significant differences (Groups B and C vs. A or control, P<0.05). In vitro MTT assay showed that cell viability rates were greater than 100% in the medium containing CsA concentrations of less than 10−7 mol/liter. However, a cytostatic effect of CsA was apparent at higher concentrations. In contrast to the previous in vivo finding of a cytostatic effect of CsA on tumor cells, we found a cytoproliferative action when CsA was administered early in the course of metastatic tumor implantation in the liver. The mechanism of cytoproliferative effect of CsA is unknown but may involve multiple factors.
Effects of Combined Treatment with Phenolic Compounds and Sodium Nitrite on Two‐stage Carcinogenesis and Cell Proliferation in the Rat Stomach
Authors: Kawabe Mayumi , Takaba Katsumi , Yoshida Yasunori , Hirose Masao
Published: August 2005

The effects of combined treatment with NaNO2 and phenolic compounds on N‐methyl‐N‐nitro‐N‐nitrosoguanidine (MNNG) stomach Carcinogenesis were investigated in F344 rats. In the first experiment, groups of 15–20 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 wk later, were given 2.0% butylated hydroxyanisole, 0.8% catechol, 2.0% 3‐methoxycatechol or basal diet either alone or in combination with 0.2% NaNO2 in the drinking water until they were killed at week 52. All three antioxidants significantly enhanced forestomach Carcinogenesis without any effect of additional NaNO2 treatment. However, in the absence of MNNG pretreatment, the grade of forestomach hyperplasia in the catechol and 3‐raethoxycatechol groups was significantly increased by the combined treatment with NaNO2. In a second experiment, the combined effects of various phenolic compounds and NaNO2 on cell proliferation in the upper digestive tract were examined. Groups of 5 rats were given one of 24 phenolic compounds or basal diet either alone or in combination with 0.3% NaNO2 for 4 weeks and then killed. Particularly strong enhancing effects in terms of thickness of the forestomach mucosa were seen with t‐butylhydroquinone (TBHQ), catechol, gallic acid, 1,2,4‐benzenetriol, dl‐3‐(3,4‐dihydroxyphenyl)‐alanine and hydroquinone in combination with NaNOi. In the glandular stomach, similar enhancing effects were evident in 11 cases, and in the esophagus with phenol, TBHQ and gallic acid. These results demonstrate that NaNO2 can augment cell proliferation induced in the stomach epithelium by various phenolic compounds.
Effects of Epidermal Growth Factor on Invasiveness through the Extracellular Matrix in High‐ and Low‐metastatic Clones of RCT Sarcoma in vitro
Authors: Yudoh Kazuo , Matsui Hisao , Kanamori Masahiko , Maeda Akio , Ohmori Kazuo , Tsuji Haruo
Published: August 2005

We investigated the invasiveness of tumor cells through the extracellular matrix and the influence of epidermal growth factor (EGF) on tumor cell invasion using in vitro systems in high‐[RCT(+)] and low‐metastatic [RCT(–)] clones established from poorly differentiated murine RCT sarcoma in C3H/He mice. In the invasion assay using a filter coated with reconstituted basement membrane (Matrigel) in a Boyden chamber, RCT(+) cells were more invasive than RCT(‐) cells. The attachment of RCT(+) cells to extracellular matrix components and the degradation of type IV collagen by the cells were significantly greater than with RCT(–) cells. However, there was no significant difference in the migration of cells to the extracellular matrix components between cultured RCT(+) and RCT(‐) cells. These findings suggested that the different invasiveness of these clone cells was associated with the difference in the ability of attachment to and degradation of the matrix. The level of laminin receptor expression in RCT(+) cells was about four‐fold that in RCT(–) cells and laminin stimulated the type IV collagenolytic activity of RCT(+) cells, suggesting that RCT(+) cell attachment to laminin via laminin receptor on the cell surface induced the production of type IV collagenase by the tumor cells. EGF did not affect the invasiveness of RCT(–) cells. In RCT(+) cells, EGF stimulated the invasiveness through Matrigel, the attachment to extracellular matrix components and the degradation of type IV collagen through high‐affinity EGF receptors (EGFR), with Kt of pM order, while the migration to the matrix was not influenced by EGF. These findings suggest that the stimulatory effect of EGF on invasion is related to the acceleration of cell adhesion, and the degradative cascade of the extracellular matrix and high‐affinity EGFRs play an important role in the effect of EGF on in vitro invasiveness in this tumor.