bluuebunny/crossref_metadata_2025 huggingface dataset:
Field emission enhancement in nitrogen-ion-implanted ultrananocrystalline diamond films
Authors: Joseph P. T. , Tai N. H. , Lee Chi-Young , Niu H. , Pong W. F. , Lin I. N.
Published: March 2008

Enhanced electron field emission (EFE) properties for ultrananocrystalline diamond (UNCD) films grown on silicon substrate were achieved, especially due to the high dose N ion implantation. Secondary ion mass spectroscopy, Raman spectroscopy, and x-ray photoelectron spectroscopy measurements indicated that the N ion implantation first expelled H−, induced the formation of disordered carbon (or defect complex), and then induced the amorphous phase, as the ion implantation dose increased. The postimplantation annealing process healed the atomic defects, but converted the disordered carbon to a stable defect complex, and amorphous carbon into a more stable graphitic phase. The EFE characteristics of the high dose (>1015ions∕cm2) ion-implanted UNCD were maintained at an enhanced level, whereas those of the low dose (<1014ions∕cm2) ion-implanted ones were reverted to the original values after the annealing process. Ion implantation over a critical dose (1×1015ions∕cm2) was required to improve the EFE properties of UNCD films.
Room temperature ferromagnetism in ZnO films due to defects
Authors: Xu Qingyu , Schmidt Heidemarie , Zhou Shengqiang , Potzger Kay , Helm Manfred , Hochmuth Holger , Lorenz Michael , Setzer Annette , Esquinazi Pablo , Meinecke Christoph , Grundmann Marius
Published: March 2008

ZnO films were prepared by pulsed laser deposition on a-plane sapphire substrates under N2 atmosphere. Ferromagnetic loops were obtained with the superconducting quantum interference device at room temperature, which indicate a Curie temperature much above room temperature. No clear ferromagnetism was observed in intentionally Cu-doped ZnO films. This excludes that Cu doping into ZnO plays a key role in tuning the ferromagnetism in ZnO. 8.8% negative magnetoresistance probed at 5K at 60kOe on ferromagnetic ZnO proves the lack of s-d exchange interaction. Anomalous Hall effect (AHE) was observed in ferromagnetic ZnO as well as in nonferromagnetic Cu-doped ZnO films, indicating that AHE does not uniquely prove ferromagnetism. The observed ferromagnetism in ZnO is attributed to intrinsic defects.
Surface passivation oxide effects on the current gain of 4H-SiC bipolar junction transistors
Authors: Lee H.-S. , Domeij M. , Zetterling C.-M. , Östling M. , Allerstam F. , Sveinbjörnsson E. Ö.
Published: March 2008

Effects of surface recombination on the common emitter current gain have been studied in 4H-silicon carbide (SiC) bipolar junction transistors (BJTs) with passivation formed by conventional dry oxidation and with passivation formed by dry oxidation in nitrous oxide (N2O) ambient. A gradual reduction of the current gain was found after removal of the passivation oxide followed by air exposure. Comparison of the measurement results for two different passivated BJTs indicates that the BJTs with passivation by dry oxidation in nitrous oxide (N2O) ambient show a half order of magnitude reduction of base current, resulting in a half order of magnitude increase of current gain at low currents. This improvement of current gain is attributed to reduced surface recombination caused by reduced interface trap densities at the base-emitter junction sidewall.
Dark-field imaging is demonstrated with a conventional hard-x-ray source
Authors: Schwarzschild Bertram
Published: March 2008

Until now x-ray images with the revealing contrast afforded by dark-field techniques could only be gotten at synchrotron light sources.
Elementary excitations in spin ice take the form of magnetic monopoles
Authors: Wilson Mark
Published: March 2008

A magnet has two poles—north and south. But in a frustrated magnetic state known as spin ice, the familiar magnetic dipole can split into two magnetic charges that independently diffuse around the crystal.
Persisting Effect of Prior Experience of Change Blindness
Authors: Takahashi Kohske , Watanabe Katsumi
Published: March 2008

Most cognitive scientists know that an airplane tends to lose its engine when the display is flickering. How does such prior experience influence visual search? We recorded eye movements made by vision researchers while they were actively performing a change-detection task. In selected trials, we presented Rensink's familiar ‘airplane’ display, but with changes occurring at locations other than the jet engine. The observers immediately noticed that there was no change in the location where the engine had changed in the previous change-blindness demonstration. Nevertheless, eye-movement analyses indicated that the observers were compelled to look at the location of the unchanged engine. These results demonstrate the powerful effect of prior experience on eye movements, even when the observers are aware of the futility of doing so.
RNA-dependent lipid remodeling by bacterial multiple peptide resistance factors
Authors: Roy Hervé , Ibba Michael
Published: February 2008

Multiple peptide resistance (MprF) virulence factors control cellular permeability to cationic antibiotics by aminoacylating inner membrane lipids. It has been shown previously that one class of MprF can use Lys-tRNA
Lys
to modify phosphatidylglycerol (PG), but the mechanism of recognition and possible role of other MprFs are unknown. Here, we used an
in vitro
reconstituted lipid aminoacylation system to investigate the two phylogenetically distinct MprF paralogs (MprF1 and MprF2) found in the bacterial pathogen
Clostridium perfringens.
Although both forms of MprF aminoacylate PG, they do so with different amino acids; MprF1 is specific for Ala-tRNA
Ala
, and MprF2 utilizes Lys-tRNA
Lys
. This provides a mechanism by which the cell can fine tune the charge of the inner membrane by using the neutral amino acid alanine, potentially providing resistance to a broader range of antibiotics than offered by lysine modification alone. Mutation of tRNA
Ala
and tRNA
Lys
had little effect on either MprF activity, indicating that the aminoacyl moiety is the primary determinant for aminoacyl-tRNA recognition. The lack of discrimination of the tRNA is consistent with the role of MprF as a virulence factor, because species-specific differences in tRNA sequence would not present a barrier to horizontal gene transfer. Taken together, our findings reveal how the MprF proteins provide a potent virulence mechanism by which pathogens can readily acquire resistance to chemically diverse antibiotics.
Prospective study to assess risk factors for pelvic floor dysfunction after delivery
Authors: SERATI MAURIZIO , SALVATORE STEFANO , KHULLAR VIK , UCCELLA STEFANO , BERTELLI EVELINA , GHEZZI FABIO , BOLIS PIERFRANCESCO
Published: February 2008

Background. To identify obstetric risk factors for de novo pelvic floor disorders after vaginal delivery. Methods. Antenatally asymptomatic women who delivered vaginally were interviewed on urinary, anal and sexual disorders antenatally, 6 and 12 months postpartum. Results. Of 967 women, 336 were included for final analysis. Urinary symptoms occurred in 27 and 23% of women at 6 and 12 months postpartum: univariate analysis showed a significant relation to the use of epidural analgesia (p =0.04) and to a second stage of labour >1 h (p =0.02), the latter was confirmed significant by multivariate analysis. Anal incontinence occurred in 7.1 and 6.8% of women at 6 and 12 months postpartum, respectively. Dyspareunia was reported by 24% at 6 months, decreasing to 8% at 12 months (p <0.0001). Conclusions. Our study shows that a second stage longer than 1 h is associated with the development of postpartum urinary incontinence. Except for dyspareunia, pelvic floor dysfunction rarely resolves spontaneously.
Prevalence of maternal group B streptococcal colonisation in European countries
Authors: BARCAITE EGLE , BARTUSEVICIUS ARNOLDAS , TAMELIENE RASA , KLIUCINSKAS MINDAUGAS , MALECKIENE LAIMA , NADISAUSKIENE RUTA
Published: February 2008

Background. Group B streptococcus (GBS) is a leading cause of neonatal sepsis in many industrialised countries. However, the burden of perinatal GBS disease varies between these countries. We undertook a systematic review to determine the prevalence of maternal group B streptococcal colonisation, one of the most important risk factor for early onset neonatal infection, and to examine the serotype distribution of the GBS strains isolated and their susceptibility to antibiotics in European countries. Methods. We followed the standard methodology for systematic reviews. We prepared a protocol and a form for data extraction that identifies key characteristics on study and reporting quality. The search was conducted for the years 1996–2006 including electronic, hand searching and screening of reference lists. Results. Twenty‐one studies presented data on 24,093 women from 13 countries. Among all studies, GBS vaginal colonisation rates ranged from 6.5 to 36%, with one‐third of studies reporting rates of 20% or greater. The regional carriage rates were as follows: Eastern Europe 19.7–29.3%, Western Europe 11–21%, Scandinavia 24.3–36%, and Southern Europe 6.5–32%. GBS serotypes III, II and Ia were the most frequently identified serotypes. None of the GBS isolates were resistant to penicillin or ampicillin, whereas 3.8–21.2% showed resistance to erythromycin and 2.7–20% showed resistance to clindamycin. Conclusion. Although there is variation in the proportion of women colonised with GBS, the range of colonisation, the serotype distribution and antimicrobial susceptibility reported from European countries appears to be similar to that identified in overseas countries.
Symptoms of Influenza Virus Infection in Hospitalized Patients
Authors: van den Dool C. , Hak E. , Wallinga J. , van Loon A. M. , Lammers J. W. J. , Bonten M. J. M.
Published: February 2008

Background.

During influenza outbreaks, fever and cough are the most accurate symptoms in predicting influenza virus infection in the community.

Objective.

To determine the usefulness of fever, cough, and other symptoms for diagnosing influenza virus infection in hospitalized patients.

Design.

Prospective cohort study.

Setting.

Three wards (pulmonology, internal medicine and infectious diseases, and geriatrics) of a tertiary care hospital in the Netherlands.

Patients.

All patients staying in the wards during peak national influenza activity in the 2005-2006 and 2006-2007 influenza seasons.

Methods.

During peak influenza activity, the presence of fever, cough, and/or other symptoms possibly associated with influenza was monitored for all patients, and nose and throat swab samples were taken twice weekly for virologic analysis.

Results.

Of 264 patients, 23 (9%) tested positive for influenza virus. The positive predictive value of fever and cough for the diagnosis of influenza virus infection was 23% (95% confidence interval, 0%-62%), and the sensitivity was 35% (95% confidence interval, 11%-58%). The combination of symptoms with the highest positive predictive value (40%) was that of cough, chills, and obstructed nose or coryza. The combination of cough and chills or fever had the highest sensitivity (60%). None of the combinations of symptoms had both a positive predictive value and a sensitivity higher than 40%.

Conclusions.

Both the sensitivity and the positive predictive value of fever, cough, and/or other symptoms for the diagnosis of influenza virus infection in hospitalized patients are low. The use of these common symptoms for treatment decisions and infection control management will probably be insufficient to contain a nosocomial outbreak, because many influenza cases will remain unidentified.
The effect of sequence quality on sequence alignment
Authors: Malde Ketil
Published: February 2008

Motivation: The nucleotide sequencing process produces not only the sequence of nucleotides, but also associated quality values. Quality values provide valuable information, but are primarily used only for trimming sequences and generally ignored in subsequent analyses.

Results: This article describes how the scoring schemes of standard alignment algorithms can be modified to take into account quality values to produce improved alignments and statistically more accurate scores. A prototype implementation is also provided, and used to post-process a set of BLAST results. Quality-adjusted alignment is a natural extension of standard alignment methods, and can be implemented with only a small constant factor performance penalty. The method can also be applied to related methods including heuristic search algorithms like BLAST and FASTA.

Availability: Software is available at http://malde.org/~ketil/qaa.

Contact:  ketil.malde@imr.no

Supplementary information: Supplementary data are available at Bioinformatics online.
Disease association tests by inferring ancestral haplotypes using a hidden markov model
Authors: Su Shu-Yi , Balding David J. , Coin Lachlan J.M.
Published: February 2008

Motivation: Most genome-wide association studies rely on single nucleotide polymorphism (SNP) analyses to identify causal loci. The increased stringency required for genome-wide analyses (with per-SNP significance threshold typically ≈ 10−7) means that many real signals will be missed. Thus it is still highly relevant to develop methods with improved power at low type I error. Haplotype-based methods provide a promising approach; however, they suffer from statistical problems such as abundance of rare haplotypes and ambiguity in defining haplotype block boundaries.

Results: We have developed an ancestral haplotype clustering (AncesHC) association method which addresses many of these problems. It can be applied to biallelic or multiallelic markers typed in haploid, diploid or multiploid organisms, and also handles missing genotypes. Our model is free from the assumption of a rigid block structure but recognizes a block-like structure if it exists in the data. We employ a Hidden Markov Model (HMM) to cluster the haplotypes into groups of predicted common ancestral origin. We then test each cluster for association with disease by comparing the numbers of cases and controls with 0, 1 and 2 chromosomes in the cluster. We demonstrate the power of this approach by simulation of case-control status under a range of disease models for 1500 outcrossed mice originating from eight inbred lines. Our results suggest that AncesHC has substantially more power than single-SNP analyses to detect disease association, and is also more powerful than the cladistic haplotype clustering method CLADHC.

Availability: The software can be downloaded from http://www.imperial.ac.uk/medicine/people/l.coin

Contact:  I.coin@imperial.ac.uk

Supplementary Information: Supplementary data are available at Bioinformatics online.
Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity
Authors: Zhao Xinyang , Jankovic Vladimir , Gural Alexander , Huang Gang , Pardanani Animesh , Menendez Silvia , Zhang Jin , Dunne Richard , Xiao Andrew , Erdjument-Bromage Hediye , Allis C. David , Tempst Paul , Nimer Stephen D.
Published: March 2008

RUNX1/AML1 is required for the development of definitive hematopoiesis, and its activity is altered by mutations, deletions, and chromosome translocations in human acute leukemia. RUNX1 function can be regulated by post-translational modifications and protein–protein interactions. We show that RUNX1 is arginine-methylated in vivo by the arginine methyltransferase PRMT1, and that PRMT1 serves as a transcriptional coactivator for RUNX1 function. Using mass spectrometry, and a methyl-arginine-specific antibody, we identified two arginine residues (R206 and R210) within the region of RUNX1 that interact with the corepressor SIN3A and are methylated by PRMT1. PRMT1- dependent methylation of RUNX1 at these arginine residues abrogates its association with SIN3A, whereas shRNA against PRMT1 (or use of a methyltransferase inhibitor) enhances this association. We find arginine-methylated RUNX1 on the promoters of two bona fide RUNX1 target genes, CD41 and PU.1 and show that shRNA against PRMT1 or RUNX1 down-regulates their expression. These arginine methylation sites and the dynamic regulation of corepressor binding are lost in the leukemia-associated RUNX1–ETO fusion protein, which likely contributes to its dominant inhibitory activity.
Myostatin promotes the terminal differentiation of embryonic muscle progenitors
Authors: Manceau Marie , Gros Jérôme , Savage Kathleen , Thomé Virginie , McPherron Alexandra , Paterson Bruce , Marcelle Christophe
Published: March 2008

Myostatin, a TGF-β family member, is an important regulator of adult muscle size. While extensively studied in vitro, the mechanisms by which this molecule mediates its effect in vivo are poorly understood. We addressed this question using chick and mouse embryos. We show that while myostatin overexpression in chick leads to an exhaustion of the muscle progenitor population that ultimately results in muscle hypotrophy, myostatin loss of function in chick and mouse provokes an expansion of this population. Our data demonstrate that myostatin acts in vivo to regulate the balance between proliferation and differentiation of embryonic muscle progenitors by promoting their terminal differentiation through the activation of p21 and MyoD. Previous studies have suggested that myostatin imposes quiescence on muscle progenitors. Our data suggest that myostatin’s effect on muscle progenitors is more complex than previously realized and is likely to be context-dependent. We propose a novel model for myostatin mode of action in vivo, in which myostatin affects the balance between proliferation and differentiation of embryonic muscle progenitors by enhancing their differentiation.
Design of a highly specific and noninvasive biosensor suitable for real‐time in vivo imaging of mercury (II) uptake
Authors: Chapleau Richard R. , Blomberg Rebecca , Ford Peter C. , Sagermann Martin
Published: February 2008

Mercury is a ubiquitous pollutant that when absorbed is extremely toxic to a wide variety of biochemical processes. Mercury (II) is a strong, “invisible” poison that is rapidly absorbed by tissues of the intestinal tract, kidneys, and liver upon ingestion. In this study, a novel fluorescence‐based biosensor is presented that allows for the direct monitoring of the uptake and distribution of the metal under noninvasive in vivo conditions. With the introduction of a cysteine residue at position 205, located in close proximity to the chromophore, the green fluorescent protein (GFP) from Aequorea victoria was converted into a highly specific biosensor for this metal ion. The mutant protein exhibits a dramatic absorbance and fluorescence change upon mercuration at neutral pH. Absorbance and fluorescence properties with respect to the metal concentration exhibit sigmoidal binding behavior with a detection limit in the low nanomolar range. Time‐resolved binding studies indicate rapid subsecond binding of the metal to the protein. The crystal structures obtained of mutant eGFP205C indicate a possible access route of the metal into the core of the protein. To our knowledge, this engineered protein is a first example of a biosensor that allows for noninvasive and real‐time imaging of mercury uptake in a living cell. A major advantage is that its expression can be genetically controlled in many organisms to enable unprecedented studies of tissue specific mercury uptake.
Establishment of a novel specific ELISA system for rat N‐ and C‐ERC/mesothelin. Rat ERC/mesothelin in the body fluids of mice bearing mesothelioma
Authors: Hagiwara Yoshiaki , Hamada Yukiko , Kuwahara Maki , Maeda Masahiro , Segawa Tatsuya , Ishikawa Kiyoshi , Hino Okio
Published: February 2008

Mesothelioma is a type of malignant tumor that most commonly arises from the pleural or peritoneal membrane and is usually associated with previous exposure to asbestos. In humans, ERC/mesothelin is expressed on the normal mesothelium and in some cancers such as mesothelioma or ovarian carcinoma. Recently, several enzyme‐linked immunosorbent assay (ELISA) systems for ERC/mesothelin have been developed, the reported usefulness of which has been assessed and demonstrated as a diagnostic tool. However, the basic roles or physiological functions of, and relationship between, ERC/mesothelin and asbestos exposure–mediated carcinogenesis remain to be resolved. In order to elucidate the precise mechanism, animal models of mesothelioma are desperately needed. In this study, we consider the development of a novel specific ELISA system for not only rat N‐ERC/mesothelin but also C‐ERC/mesothelin, and the first data on the presence of rat ERC/mesothelin in the body fluids of rat malignant mesothelioma–bearing nude mice. The transplanted mice have revealed the higher concentrations of rat N‐ERC/mesothelin in the blood and ascites than C‐ERC/mesothelin. We hope these novel ELISA systems are useful in the rat model system to clarify the mechanism of asbestos‐induced carcinogenesis and to develop new effective drugs for mesothelioma. (Cancer Sci 2008; 99: 666–670)
Cell‐death‐inducing monoclonal antibodies raised against DT40 tumor cells: Identification of chicken transferrin receptor as a novel cell‐death receptor
Authors: Ohno Yoshiya , Yagi Hideki , Nakamura Masanori , Masuko Kazue , Hashimoto Yoshiyuki , Masuko Takashi
Published: February 2008

We obtained unique cell‐death‐inducing monoclonal antibodies (mAbs) named D18 and D19 against chicken DT40 cells. D18 and D19 caused several signs of apoptosis, such as exposed phosphatidyl serine on the cell surface, a sub G0/G1 peak, and DNA fragmentation, and inhibited the proliferation of DT40 cells. Flow cytometric and immunohistological analyses of various normal chicken tissues revealed the expression of the antigen recognized by these mAbs to be restricted to cells in lymphoid organs including bone marrow and bursa of fabricius, and to cells in some epithelial tissues. The cell death induced by the mAbs progressed through a mitochondrial pathway with loss of mitochondrial membrane potential. Apoptosis is generally characterized by cell shrinking; however, D18 and D19 elicited swelling, which preceded the cell death. We analyzed the antigen immunoprecipitated by the mAbs, and identified a 90‐ to 100‐kDa cell‐surface glycoprotein as the chicken transferrin receptor (TfR). Epitopes recognized by the two mAbs were confirmed to be different by the binding inhibition assay. The reactivity of the mAbs against DT40 cells was not inhibited by excess chicken serum, suggesting that the cell death induced by D18 and D19 was not caused by inhibition of the binding of transferrin (Tf) to chicken TfR. Since D18 and D19 have induced cell death in human embryonic kidney cells transfected with cDNA of the full‐length chicken TfR, we expect human TfR to be a promising target in antibody therapy for various human malignancies. (Cancer Sci 2008; 99: 894–900)
Reactivation of p53 in cells expressing hepatitis B virus X‐protein involves p53 phosphorylation and a reduction of Hdm2
Authors: Wang Jin‐Hee , Yun Chawon , Kim Sujeong , Chae Sunyoung , Lee Young Ik , Kim Wook‐Hwan , Lee Jae‐Ho , Kim Wankee , Cho Hyeseong
Published: February 2008

Multifunctional activities of the hepatitis B virus X‐protein (HBx) in cells have been largely implicated in the development of liver cancer; one of these activities is the loss of p53 function by sequestering p53 in the cytoplasm. We have previously found that doxorubicin increased the p53 levels in cells containing p53‐binding HBx protein and restored the p53‐mediated transcriptional activity that was suppressed by HBx. Here, we investigated the mechanism underlying p53 reactivation. We found that six phosphorylation sites of the Serine residues of p53 were efficiently phosphorylated in HBx‐expressing ChangX‐34 cells, suggesting that the binding of HBx to the p53 protein does not interfere with the phosphorylation of p53 by signaling kinases. In addition, doxorubicin caused a dramatic reduction of Hdm2 mRNA and protein levels in cells expressing HBx. Intriguingly, reactivation of p53 was accompanied with a nuclear accumulation of p53 and the phosphorylated p53 at Serine15 was only detected in nuclear fraction, but not in cytosolic fraction of doxorubicin‐treated ChangX‐34 cells. Functional restoration of the p53 protein in HBx‐expressing cells occurs according to the dual effects of doxorubicin: a significant reduction of Hdm2 expression and a nuclear accumulation of the phosphorylated p53 protein. Thus, proper usage of doxorubicin as an effective antitumor agent may be reevaluated and can be extended to tumors primarily caused by infection of DNA tumor viruses. (Cancer Sci2008; 99: 888–893)
Direct visualization and quantification of the anticancer agent, cis‐diamminedichloro‐platinum(II), in human lung cancer cells using in‐air microparticle‐induced X‐ray emission analysis
Authors: Sakurai Hideyuki , Okamoto Masahiko , Hasegawa Masatoshi , Satoh Takahiro , Oikawa Masakazu , Kamiya Tomihiro , Arakawa Kazuo , Nakano Takashi
Published: February 2008

The authors designed an elemental analysis system using an ion microbeam combined with a microparticle‐induced X‐ray emission (micro‐PIXE) method for the analysis of biomedical samples in air with a spatial resolution of 1 µm (in‐air micro‐PIXE system). This system was used to develop an imaging and quantification method for intracellular cis‐diamminedichloro‐platinum(II) (CDDP) in a human lung cancer cell line. A human lung adenocarcinoma cell line, A549, was cultured and nuclear labeling was carried out by incubating the cells with BrdU. The cells were then exposed to CDDP at concentrations ranging from 1 µmol to 1 mmol, for 30 min to 24 h. After drug treatment, samples were washed and frozen with liquid nitrogen, and freeze‐dried for 24 h. Standard samples were made using agar containing several concentrations of CDDP. Experiments using standard samples showed a linear correlation between CDDP concentration and platinum signal strength. No clear platinum signal was detected after exposure to CDDP for 24 h at doses between 1 and 100 µmol. However, significant platinum signals were observed at 1 mmol. When nucleus and cytoplasm visualization was sufficiently clear to efficiently use in‐air micro‐PIXE, the platinum image quality was considered satisfactory. The detected signals of CDDP were stronger in the nucleus than in the cytoplasm. A time‐course study showed increased CDDP uptake in cells after longer drug exposure periods. The present study demonstrates the application of element analysis using in‐air micro‐PIXE to biomedical samples. The use of this system enables the high‐resolution visualization of intracellular CDDP distribution and measurement of intracellular CDDP concentrations. (Cancer Sci 2008; 99: 901–904)
Identification of candidate cooperative genes of the Apc mutation in transformation of the colon epithelial cell by retroviral insertional mutagenesis
Authors: Tanaka Miwa , Jin Guang , Yamazaki Yukari , Takahara Tomoko , Takuwa Miki , Nakamura Takuro
Published: February 2008

The mutation of Apc is an important early genetic event in colon carcinogenesis. However, it remains to be clarified what kinds of cooperative genes are required for complete carcinogenesis. To identify cooperative genes for the ApcMin mutation the authors carried out retroviral insertional mutagenesis (RIM) using Min mouse‐derived IMCE colon epithelial cells. Anchorage‐independent transformed colonies were induced by retroviral infection only in IMCE cells, while no transformation was found in young adult mouse colon (YAMC) cells that are normal for Apc. One hundred and fifty‐seven retroviral integration sites (RIS) were identified in 101 independent transformants, and four common integration sites (CIS), Dnah3, Ahnak, Stk17b and Rbm9, were observed. Upregulation of Dnah3 and Ahnak, and truncation of Dnah3 due to the viral integration, was revealed. In addition, Dnah3‐overexpressing IMCE cells showed impairment of microtubule function. These data suggest the importance of cytoskeletal function in Apc‐related tumor development and the usefulness of RIM in non‐hematopoietic tissues, providing new insight into the early stage of colon carcinogenesis. (Cancer Sci 2008; 99: 979–985)
Antineovascular therapy with angiogenic vessel‐targeted polyethyleneglycol‐shielded liposomal DPP–CNDAC
Authors: Asai Tomohiro , Miyazawa Souichiro , Maeda Noriyuki , Hatanaka Kentaro , Katanasaka Yasufumi , Shimizu Kosuke , Shuto Satoshi , Oku Naoto
Published: February 2008

Causing damage to angiogenic vessels is a promising approach for cancer chemotherapy. The present study is a codification of a designed liposomal drug delivery system (DDS) for antineovascular therapy (ANET) with 2′‐C‐cyano‐2′‐deoxy‐1‐β‐D‐arabino‐pentofuranosylcytosine (CNDAC). The authors have previously reported that liposomalized 5′‐O‐dipalmitoylphosphatidyl CNDAC (DPP–CNDAC), a phospholipid derivative of the novel antitumor nucleoside CNDAC, is quite useful for ANET. DPP–CNDAC liposomes modified with APRPG, a peptide having affinity toward angiogenic vessels, efficiently suppressed tumor growth by damaging angiogenic endothelial cells. In the present study, the authors masked the hydrophilic moiety of DPP–CNDAC, namely, CNDAC, on the liposomal surface with APRPG–polyethyleneglycol (PEG) conjugate to improve the availability of DPP–CNDAC liposomes. The use of the APRPG–PEG conjugate attenuated the negative ζ‐potential of the DPP–CNDAC liposomes and reduced the agglutinability of them in the presence of serum. These effects improved the blood level of DPP–CNDAC liposomes in colon 26 NL‐17 tumor‐bearing BALB/c male mice, resulting in enhanced accumulation of them in the tumor. Laser scanning microscopic observations indicated that APRPG–PEG‐modified DPP–CNDAC liposomes (LipCNDAC/APRPG–PEG) colocalized with angiogenic vessels and strongly induced apoptosis of tumor cells, whereas PEG‐modified DPP–CNDAC liposomes (LipCNDAC/PEG) did not. In fact, LipCNDAC/APRPG–PEG suppressed the tumor growth more strongly compared to LipCNDAC/PEG and increased significantly the life span of the mice. The present study is a good example of an effective liposomal DDS for ANET that is characterized by: (i) phospholipid derivatization of a certain anticancer drug to suit the liposomal formulation; (ii) PEG‐shielding for masking undesirable properties of the drug on the liposomal surface; and (iii) active targeting to angiogenic endothelial cells using a specific probe. (Cancer Sci 2008; 99: 1029–1033)
Co‐administration of carcinoembryonic antigen and HIV TAT fusion protein with CpG‐oligodeoxynucleotide induces potent antitumor immunity
Authors: Woo Sun‐Je , Kim Chang‐Hyun , Park Mi‐Young , Kim Hye‐Sung , Sohn Hyun‐Jung , Park Jung‐Sun , Kim Hyung‐Jin , Oh Seong‐Taek , Kim Tai‐Gyu
Published: February 2008

Although dendritic cells (DC) have been well demonstrated as a strong cellular adjuvant for a tumor vaccine, there are several limitations for clinical application. A protein‐based vaccine using a potent adjuvant is an appealing approach for tumor antigen‐specific immunotherapy because of their simplicity, safety, efficacy and capacity for repeated administration. CpG‐oligodeoxynucleotides (ODN) have been used as adjuvants to stimulate innate and adaptive immune responses for cancer treatment. The authors evaluated the adjuvant effects of CpG‐ODN in a vaccine incorporating recombinant fusion protein of the HIV TAT PTD domain and carcinoembryonic antigen (TAT‐CEA). Mice vaccinated with TAT‐CEA and CpG‐ODN (TAT‐CEA + CpG) showed enhanced CEA‐specific immunity, including cytotoxic T‐lymphocytes (CTL) activity and interferon (IFN)‐γ secreting T cells compared with CEA and CpG‐ODN (CEA + CpG) or TAT‐CEA vaccination alone. Vaccination with TAT‐CEA + CpG elicited Th1‐based responses, as indicated by the higher ratio of immunoglobulin (Ig)G2a antibody/IgG1 antibodies specific for CEA. The survival rate was significantly increased after vaccination with TAT‐CEA + CpG in a tumor model using MC38/CEA2. Furthermore, the TAT‐CEA ± CpG vaccine groups showed similar antitumor immunity to the CEA peptide‐pulsed DC (CEA peptide/DC) vaccine groups. These data suggest that coadministration of TAT fusion protein with CpG‐ODN may serve as a potential formulation for enhancing antitumor activity. (Cancer Sci 2008; 99: 1034–1039)
Inflammation and cancer: Role of nuclear factor‐kappaB activation
Authors: Maeda Shin , Omata Masao
Published: February 2008

It has been thought that there is a strong relationship between inflammation and carcinogenesis so that the development of cancer occurs with chronic inflammation in many organs. An in‐depth understanding of the mechanism by which inflammation can lead to carcinogenesis may enable the development of drugs targeted at important molecules, providing a powerful tool for preventing cancer development. In this review, we focused on a signal transduction system, the nuclear factor‐kappaB (NF‐κB) pathway, which is thought to play a role in the process leading from inflammation to carcinogenesis, and may thus serve as a candidate for targeted intervention. (Cancer Sci 2008; 99: 836–842)
Proteasome inhibitors remarkably prevent translesion replication in cancer cells but not normal cells
Authors: Takezawa Jun , Ishimi Yukio , Yamada Kouichi
Published: February 2008

When a replicative DNA polymerase encounters a lesion on the template strand and stalls, it is replaced with another polymerase(s) with low processivity that bypasses the lesion to continue DNA synthesis. This phenomenon is known as translesion replication or replicative bypass. Failing this, the cell is increasingly likely to undergo apoptosis. In this study, we found that proteasome inhibitors prevent translesion replication in human cancer cells but not in normal cells. Three proteasome inhibitors, MG‐132, lactacystin, and MG‐262, inhibited UV‐induced translesion replication in a wide range of cancer cell lines, including HeLa, HGC‐27, MCF‐7, HepG2, WiDr, a malignant melanoma, an acute lymphoblastic leukemia, and a multiple myeloma cell line; irrespective of cell origin, histological type, or p53 status. In contrast, these inhibitors had little or no influence on normal fibroblasts (NB1RGB and TIG‐1) or a normal liver mesenchymal (LI90) cell line. Among the DNA‐damaging antineoplastic agents, cisplatin caused a UV‐type translesion reaction; the proteasome inhibitors delayed cisplatin‐induced translesion replication in cancer cell lines but had only a weak effect on normal cell lines. Therefore, translesion replication would be an effective target of proteasome inhibitors for cancer chemotherapy by which cancer cells can be efficiently sensitized to DNA‐damaging antineoplastic agents, such as cisplatin. (Cancer Sci 2008; 99: 863–871)
DNA chip databases, omics, and gene fishing: Commentary
Authors: Jakt Lars Martin , Nishikawa Shinichi
Published: February 2008

(Cancer Sci 2008; 99: 829–835)
Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma
Authors: Imai Takashi , Toyota Minoru , Suzuki Hiromu , Akino Kimishige , Ogi Kazuhiro , Sogabe Yohei , Kashima Lisa , Maruyama Reo , Nojima Masanori , Mita Hiroaki , Sasaki Yasushi , Itoh Fumio , Imai Kohzoh , Shinomura Yasuhisa , Hiratsuka Hiroyoshi , Tokino Takashi
Published: February 2008

Genetic and epigenetic alterations in tumor‐suppressor genes play important roles in human neoplasia. Ras signaling is often activated in oral squamous cell carcinoma (OSCC), although Ras mutations are rarely detected in Japanese OSCC patients, and the mechanisms underlying the gene's activation remain unclear. Here, we examined the expression of Ras association family (RASSF) genes in a panel of OSCC cell lines and found that RASSF2 is often downregulated by DNA methylation in OSCC cells. In addition, aberrant methylation of RASSF2 was detected in 12 of 46 (26%) primary OSCC, and 18 (39%) of those OSCC showed methylation of at least one RASSF gene. Ectopic expression of RASSF2 in OSCC cells suppressed cell growth and induced apoptosis. A RASSF2 deletion mutant lacking the Ras‐association domain, which was therefore unable to interact with Ras, exhibited less pro‐apoptotic activity than the full‐length protein, indicating that the pro‐apoptotic activity of RASSF2 is related to its association with Ras. Genomic screening of genes regulated by RASSF2 showed that genes involved in immune responses, angiogenesis, and metastasis are suppressed by RASSF2. Our results suggest that epigenetic inactivation of RASSF2 plays an important role in OSCC tumorigenesis, and that RASSF2 may be a useful molecular target for the diagnosis and treatment of OSCC. (Cancer Sci 2008; 99: 958–966)
Production and characterization of highly tumor‐specific rat monoclonal antibodies recognizing the extracellular domain of human l‐type amino‐acid transporter 1
Authors: Ohno Yoshiya , Suda Kentaro , Masuko Kazue , Yagi Hideki , Hashimoto Yoshiyuki , Masuko Takashi
Published: February 2008

l‐type large amino acid transporter (LAT) 1, the first light chain (lc) of cluster of differentiation 98 (CD98) to be identified, is associated with the heavy chain (hc) of CD98 and expressed on the surface of various tumor cells irrespective of their origin. Because LAT1 is a 12‐pass membrane protein and its possible immunogenic extracellular region is very small, specific monoclonal antibodies (mAb) had not been developed. We report the successful preparation and characterization of mAb recognizing the extracellular domain of human LAT1 protein. Two mAb were selected from hybridoma clones established by fusing mouse myeloma cells and spleen cells from rats immunized against RH7777 rat hepatoma cells expressing recombinant green fluorescent protein fused to human LAT1 protein. Designated SOL22 and SOL69, these mAb specifically reacted with the extracellular domain of LAT1 on cells transfected with cDNA of LAT1, but not with cells transfected with cDNA of other CD98 lc, namely, LAT2, y+LAT1, y+LAT2, and xCT amino acid transporters. These mAb immunoprecipitated 35‐ and 90‐kDa proteins under reducing conditions in extracts prepared from human HeLa tumor cells, indicating the existence of intermolecular disulfide bonds between cysteine residues in the 90‐kDa hc and 35‐kDa lc (LAT1). SOL22 and SOL69 mAb reacted with a wide variety of living unfixed human tumor cell lines, but were only weakly reactive with HEK293F human embryonic kidney cells and human peripheral blood cells. Comparative immunohistochemical analyses of normal human tissues with anti‐CD98 hc and anti‐LAT1 revealed LAT1 to be an excellent molecular target for antibody therapy, possibly even superior to CD98 hc. (Cancer Sci 2008; 99: 1000–1007)
Impact of CYP2D6*10 on recurrence‐free survival in breast cancer patients receiving adjuvant tamoxifen therapy
Authors: Kiyotani Kazuma , Mushiroda Taisei , Sasa Mitsunori , Bando Yoshimi , Sumitomo Ikuko , Hosono Naoya , Kubo Michiaki , Nakamura Yusuke , Zembutsu Hitoshi
Published: February 2008

The clinical outcomes of breast cancer patients treated with tamoxifen may be influenced by the activity of cytochrome P450 2D6 (CYP2D6) enzyme because tamixifen is metabolized by CYP2D6 to its active forms of antiestrogenic metabolite, 4‐hydroxytamoxifen and endoxifen. We investigated the predictive value of the CYP2D6*10 allele, which decreased CYP2D6 activity, for clinical outcomes of patients that received adjuvant tamoxifen monotherapy after surgical operation on breast cancer. Among 67 patients examined, those homozygous for the CYP2D6*10 alleles revealed a significantly higher incidence of recurrence within 10 years after the operation (P = 0.0057; odds ratio, 16.63; 95% confidence interval, 1.75–158.12), compared with those homozygous for the wild‐type CYP2D6*1 alleles. The elevated risk of recurrence seemed to be dependent on the number of CYP2D6*10 alleles (P = 0.0031 for trend). Cox proportional hazard analysis demonstrated that the CYP2D6 genotype and tumor size were independent factors affecting recurrence‐free survival. Patients with the CYP2D6*10/*10 genotype showed a significantly shorter recurrence‐free survival period (P = 0.036; adjusted hazard ratio, 10.04; 95% confidence interval, 1.17–86.27) compared to patients with CYP2D6*1/*1 after adjustment of other prognosis factors. The present study suggests that the CYP2D6 genotype should be considered when selecting adjuvant hormonal therapy for breast cancer patients. (Cancer Sci 2008; 99: 995–999)
Does constrained oviposition influence offspring sex ratio in the solitary parasitoid wasp Venturia canescens?
Authors: METZGER MARIE , BERNSTEIN CARLOS , DESOUHANT EMMANUEL
Published: March 2008

Abstract 1. In haplodiploid organisms, virgin or sperm‐depleted females can reproduce but are constrained to produce only male progeny. According to Godfray’s constrained model, when p, the proportion of females constrained to produce only male progeny, is not null in a panmictic population, unconstrained females should bias their sex allocation towards females to compensate for the excess of males. These unconstrained females should be able to adjust the sex ratio in response to local variation of p.

2. In this paper an experimental approach is used to test the hypotheses of this model in the solitary endoparasitoid Venturia canescens under both field and laboratory conditions. Specifically, it is tested whether unconstrained females use their encounters with conspecifics (either male or female) to estimate p and then adjust their sex ratio accordingly.

3. As assumed by Godfray’s model, constrained females actively search for host patches in the field and under laboratory conditions produce the same number of offspring during their lifetime as unconstrained females. As predicted by the model, unconstrained females produce a sex ratio biased towards females both in the laboratory and in the field.

4. The results show that this bias is not a response to encounters with conspecifics previous to oviposition. The hypothesis that the bias is due to differential mortality between sexes during ontogeny is also rejected. The proportions of constrained ovipositions estimated in two natural populations explain only a small fraction of the sex ratio bias observed in V. canescens.
Construct validity of a health questionnaire intended to measure the subjective experience of health among patients in mental health services
Authors: JORMFELDT H. , ARVIDSSON B. , SVENSSON B. , HANSSON L.
Published: February 2008

Mental health services have been lacking systematic health‐promoting activities, and health is often perceived as the absence of disease from a biomedical perspective. It is vital to develop methods to assess perceived health among patients in a broader perspective. The aim of the study was to investigate construct validity of a newly developed health questionnaire intended to measure subjectively experienced health among patients in mental health services. A cross‐sectional study, including a randomly selected sample of 139 outpatients in contact with the mental health services, was performed in order to explore the relationship between perceived health and self‐reported levels of self‐esteem, symptoms, empowerment, quality of life and experiences of stigmatization. Self‐esteem, symptoms, empowerment and quality of life altogether accounted for 70% of the variation in overall perceived health. Overall perceived health showed positive associations to self‐esteem, empowerment and quality of life and negative associations to psychiatric symptoms, discrimination and rejection experiences. The findings suggest that perceived health as measured by the health questionnaire can be a meaningful and valid construct that may be useful for measuring health in clinical mental healthcare practice and in mental health services research.
Paediatric allergy diagnosis in primary care is improved by in vitro allergen‐specific IgE testing
Authors: Niggemann Bodo , Nilsson Monika , Friedrichs Frank
Published: February 2008

Allergy testing is an important pre‐requisite for both early identification of infants at increased risk for later development of allergic diseases and for specific allergy treatment including specific allergen avoidance measures, pharmacotherapy and specific immunotherapy. The aim of this study was to investigate the influence of in vitro allergen‐specific immunoglobulin E (IgE) testing on the primary care physician’s diagnosis and clinical management of children with symptoms of eczema, wheezing/asthma and rhinitis. The trial was a prospective study performed at 14 paediatric primary care practices in Germany, covering 380 children below 6 yr of age. For one group of children the physician received the IgE test results as soon as possible and used them as an additional tool when diagnosing and giving clinical management advice. For the other group of children the IgE test results were not made available to the physician until the children were brought to a second visit, about 7 wk later. When diagnosis was made without access to allergen‐specific IgE results, 8% of the children were diagnosed as allergic, 6% as non‐allergic and in 86% of the cases the physician was uncertain. With access to allergen‐specific IgE results the figures were 13%, 65% and 22%, respectively. Concerning clinical management advice no statistically significant differences between the two study groups were observed. When comparing the first and second visits of the patients coming for a second visit advice to reduce aeroallergen exposure was given to 27% of the patients at visit 1 and to 36% of the patients at visit 2 (p = 0.002). The difference between the first and second visits of the other clinical management advice studied did not reach statistical significance. In this study the availability of IgE test results to the primary care physician had an impact on the decision‐making process of the diagnosis but not on the pharmaceutical or avoidance advice given. The reason why IgE test results were not fully exploited needs to be further scrutinized.
The prevalence of allergic diseases in an unselected group of 6‐year‐old children. The DARC birth cohort study
Authors: Kjaer Henrik Fomsgaard , Eller Esben , Høst Arne , Andersen Klaus Ejner , Bindslev‐Jensen Carsten
Published: March 2008

This study determines the prevalence of atopic dermatitis, asthma, rhinoconjunctivitis, food hypersensitivity and urticaria and the frequency of sensitization in children with and without clinical allergic disease. In an ongoing prospective non‐interventional birth cohort study of 562 unselected children, 404 children were subjected to interview, clinical examination, lung function measurements and allergy testing at 6 yr of age. Sensitization measured by skin prick test (SPT) and specific immunoglobulin E (S‐IgE) was determined for 24 different allergens. The 1‐yr period prevalence of atopic dermatitis, asthma and rhinoconjunctivitis was 14.4%, 6.2% and 13.6%. 25.7% of the children suffered from at least one of the three diseases. The frequency of sensitization in children with no disease (controls), any allergic disease, atopic dermatitis, asthma and rhinoconjunctivitis was 17%, 45%, 47%, 56% and 55% (defined as SPT ≥3 mm and/or S‐IgE ≥0.35 kU/l for at least one allergen). Symptoms were linked to sensitization for 44% in the asthma group and 42% in the rhinoconjunctivitis group, whereas sensitization could not be linked to worsening of the eczema in any cases of atopic dermatitis. Overlap between the three diseases was significantly more frequent in sensitized children than in non‐sensitized (19/46 = 41% vs. 9/58 = 16%, p = 0.004). The prevalence of food hypersensitivity and urticaria was 1.2% and 5.4% respectively. In unselected 6 yr old children, approximately half of the children with atopic dermatitis, asthma or rhinoconjunctivitis are IgE‐sensitized. Sensitization tends to link these diseases to each other.