bluuebunny/crossref_metadata_2025 huggingface dataset:
Array-Based Comparative Genomic Hybridization Analysis Identified Cyclin D1 as a Target Oncogene at 11q13.3 in Nasopharyngeal Carcinoma
Authors: Hui Angela Bik-Yu , Or Yvonne Yan-Yan , Takano Hirokuni , Tsang Raymond King-Yin , To Ka-Fai , Guan Xin-Yuen , Sham Jonathan Shun-Tong , Hung Katherine Wing-Ki , Lam Cleo Nga-Yee , van Hasselt Charles Andrew , Kuo Wen-Lin , Gray Joe W. , Huang Dolly P. , Lo Kwok-Wai
Published: September 2005

Nasopharyngeal carcinoma is highly prevalent in Southern China and Southeast Asia. To unveil the molecular basis of this endemic disease, high-resolution comparative genomic hybridization arrays were used for systematic investigation of genomic abnormalities in 26 nasopharyngeal carcinoma samples. A comprehensive picture of genetic lesions associated with tumorigenesis of nasopharyngeal carcinoma was generated. Consistent chromosomal gains were frequently found on 1q, 3q, 8q, 11q, 12p, and 12q. High incidences of nonrandom losses were identified on chromosomes 3p, 9p, 11q, 14q, and 16q. In addition to previously characterized regions, we have identified several novel minimal regions of gains, including 3q27.3-28, 8q21-24, 11q13.1-13.3, and 12q13, which may harbor candidate nasopharyngeal carcinoma–associated oncogenes. In this study, gain of 11q13.1-13.3 was the most frequently detected chromosomal aberration and a 5.3-Mb amplicon was delineated at this region. Within this 11q13 amplicon, concordant amplification and overexpression of cyclin D1 (CCND1) oncogene was found in nasopharyngeal carcinoma cell lines, xenografts, and primary tumors. Knockdown of cyclin D1 by small interfering RNA in nasopharyngeal carcinoma cell lines led to significant decrease of cell proliferation. The findings suggest that cyclin D1 is a target oncogene at 11q13 in nasopharyngeal carcinoma and its activation plays a significant role in nasopharyngeal carcinoma tumorigenesis.
The Fallacy of Epithelial Mesenchymal Transition in Neoplasia
Authors: Tarin David
Published: September 2005

Epithelial mesenchymal transition has been postulated as a versatile mechanism which facilitates cellular repositioning and redeployment during embryonic development, tissue reconstruction after injury, carcinogenesis, and tumor metastasis. The hypothesis originates from parallels drawn between the morphology and behavior of locomotory and sedentary cells in vitro and in various normal and pathologic processes in vivo. This review analyzes data from several studies on embryonic development, wound healing, and the pathology of human tumors, including work from our own laboratory, to assess the validity of the proposal. It is concluded that there is no convincing evidence for conversion of epithelial cells into mesenchymal cell lineages in vivo and that the biological repertoire of normal and malignant cells is sufficient to account for the events and processes observed, without needing to invoke radical changes in cell identity.
Akt Phosphorylates Tal1 Oncoprotein and Inhibits Its Repressor Activity
Authors: Palamarchuk Alexey , Efanov Alexey , Maximov Vadim , Aqeilan Rami I. , Croce Carlo M. , Pekarsky Yuri
Published: September 2005

The helix-loop-helix transcription factor Tal1 is required for blood cell development and its activation is a frequent event in T-cell acute lymphoblastic leukemia. The Akt (protein kinase B) kinase is a key player in transduction of antiapoptotic and proliferative signals in T cells. Because Tal1 has a putative Akt phosphorylation site at Thr90, we investigated whether Akt regulates Tal1. Our results show that Akt specifically phosphorylates Thr90 of the Tal1 protein within its transactivation domain in vitro and in vivo. Coimmunoprecipitation experiments showed the presence of Tal1 in Akt immune complexes, suggesting that Tal1 and Akt physically interact. We further showed that phosphorylation of Tal1 by Akt causes redistribution of Tal1 within the nucleus. Using luciferase assay, we showed that phosphorylation of Tal1 by Akt decreased repressor activity of Tal1 on EpB42 (P4.2) promoter. Thus, these data indicate that Akt interacts with Tal1 and regulates Tal1 by phosphorylation at Thr90 in a phosphatidylinositol 3-kinase–dependent manner.
Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents
Authors: Vearing Christopher , Lee Fook-Thean , Wimmer-Kleikamp Sabine , Spirkoska Violeta , To Catherine , Stylianou Con , Spanevello Mark , Brechbiel Martin , Boyd Andrew W. , Scott Andrew M. , Lackmann Martin
Published: September 2005

The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands form a unique cell-cell contact–mediated system for controlling cell localization and organization. Their high expression in a wide variety of human tumors indicates a role in tumor progression, and relatively low Eph and ephrin levels in normal tissues make these proteins potential targets for anticancer therapies. The monoclonal antibody IIIA4, previously used to isolate EphA3, binds with subnanomolar affinity to a conformation-specific epitope within the ephrin-binding domain that is closely adjacent to the “low-affinity” ephrin-A5 heterotetramerization site. We show that similar to ephrin-A5, preclustered IIIA4 effectively triggers EphA3 activation, contraction of the cytoskeleton, and cell rounding. BIAcore analysis, immunoblot, and confocal microscopy of wild-type and mutant EphA3 with compromised ephrin-A5 or IIIA4-binding capacities indicate that IIIA4 binding triggers an EphA3 conformation which is permissive for the assembly of EphA3/ephrin-A5-type signaling clusters. Furthermore, unclustered IIIA4 and ephrin-A5 Fc applied in combination initiate greatly enhanced EphA3 signaling. Radiometal conjugates of ephrin-A5 and IIIA4 retain their affinity, and in mouse xenografts localize to, and are internalized rapidly into EphA3-positive, human tumors. These findings show the biological importance of EphA3/ephrin-A5 interactions and that ephrin-A5 and IIIA4 have great potential as tumor targeting reagents.
The Glycosphingolipid, Lactosylceramide, Regulates β1-Integrin Clustering and Endocytosis
Authors: Sharma Deepak K. , Brown Jennifer C. , Cheng Zhijie , Holicky Eileen L. , Marks David L. , Pagano Richard E.
Published: September 2005

Glycosphingolipids are known to play roles in integrin-mediated cell adhesion and migration; however, the mechanisms by which glycosphingolipids affect integrins are unknown. Here, we show that addition of the glycosphingolipid, C8-lactosylceramide (C8-LacCer), or free cholesterol to human fibroblasts at 10°C causes the formation of glycosphingolipid-enriched plasma membrane domains as shown by visualizing a fluorescent glycosphingolipid probe, BODIPY-LacCer, incorporated into the plasma membrane of living cells. Addition of C8-LacCer or cholesterol to cells initiated the clustering of β1-integrins within these glycosphingolipid-enriched domains and the activation of the β1-integrins as assessed using a HUTS antibody that only binds activated integrin. On warming to 37°C, β1-integrins were rapidly internalized via caveolar endocytosis in cells treated with C8-LacCer or cholesterol, whereas little β1-integrin was endocytosed in untreated fibroblasts. Incubation of cells with C8-LacCer or cholesterol followed by warm-up caused src activation, a reorganization of the actin cytoskeleton, translocation of RhoA GTPase away from the plasma membrane as visualized using total internal reflection fluorescence microscopy, and transient cell detachment. These studies show that LacCer can regulate integrin function both by modulating integrin clustering in microdomains and by regulating integrin endocytosis via caveolae. Our findings suggest the possibility that aberrant levels of glycosphingolipids found in cancer cells may influence cell attachment events by direct effects on integrin clustering and internalization.
Chromosomal Instability in Unirradiated Hemopoietic Cells Resulting from a Delayed In vivo Bystander Effect of γ Radiation
Authors: Lorimore Sally A. , McIlrath Joanne M. , Coates Philip J. , Wright Eric G.
Published: September 2005

Untargeted effects of ionizing radiation (de novo effects in the unirradiated descendants or neighbors of irradiated cells) challenge widely held views about the mechanisms of radiation-induced DNA damage with implications for the health consequences of radiation exposures particularly in the context of the induction of malignancy. To investigate in vivo untargeted effects of sparsely ionizing (low linear energy transfer) radiation, a congenic sex-mismatch bone marrow transplantation protocol has been used to repopulate the hemopoietic system from a mixture of γ-irradiated and nonirradiated hemopoietic stem cells such that host-, irradiated donor– and unirradiated donor–derived cells can be distinguished. Chromosomal instability in the progeny of irradiated hemopoietic stem cells accompanied by a reduction in their contribution to the repopulated hemopoietic system is consistent with a delayed genomic instability phenotype being expressed in vivo. However, chromosomal instability was also shown in the progeny of the nonirradiated hemopoietic stem cells implicating a bystander mechanism. Studies of the influence of irradiated recipient stromal microenvironment and experiments replacing irradiated cells with irradiated cell–conditioned medium reveal the source of the in vivo bystander effect to be the descendants of irradiated cells, rather than irradiated cell themselves. Thus, it is possible that a radiation-induced genomic instability phenotype in vivo need not necessarily be a reflection of intrinsically unstable cells but the responses to ongoing production of inflammatory-type damaging signals as a long-term unexpected consequence of the initial single radiation exposure.
Epidermal Growth Factor Receptors Harboring Kinase Domain Mutations Associate with the Heat Shock Protein 90 Chaperone and Are Destabilized following Exposure to Geldanamycins
Authors: Shimamura Takeshi , Lowell April M. , Engelman Jeffrey A. , Shapiro Geoffrey I.
Published: September 2005

Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR), including L858R and exon 19 deletions, underlie responsiveness to gefitinib and erlotinib in non–small cell lung cancer (NSCLC). Acquired resistance to these tyrosine kinase inhibitors is in some cases mediated by a second mutation, T790M. Ansamycin antibiotics, such as geldanamycin, potently inhibit heat shock protein 90 (Hsp90), promoting ubiquitin-mediated degradation of oncogenic kinases that require the chaperone for proper conformational folding. Here, we show that L858R and deletion mutant EGFR proteins found in NSCLC interact with the chaperone and are sensitive to degradation following Hsp90 inhibition. In NIH/3T3 cells expressing either wild-type or mutant EGFR, diminution of expression of both L858R and EGFR delL747-S752, P753S occurred following exposure to 50 nmol/L geldanamycin over 24 hours, whereas partial diminution of wild-type EGFR required a minimum of 200 nmol/L drug. In time course experiments, mutant EGFR expression was depleted after only 4 hours of exposure to 1 μmol/L geldanamycin, whereas diminution of wild-type EGFR was less substantial and seen only following 12 hours. Similarly, EGFR proteins in NSCLC cell lines harboring EGFR mutations, including NCI-H1650, NCI-H3255, and NCI-H1975, were also more sensitive to geldanamycin-induced degradation compared with the protein in wild-type cells. Exposure of EGFR-mutant cell lines to geldanamycin induced marked depletion of phospho-Akt and cyclin D1 as well as apoptosis. These data suggest mutational activation of EGFR is associated with dependence on Hsp90 for stability and that Hsp90 inhibition may represent a novel strategy for the treatment of EGFR-mutant NSCLC.
Targeting of Antigens to Activated Dendritic Cells In vivo Cures Metastatic Melanoma in Mice
Authors: Mahnke Karsten , Qian Yingjie , Fondel Sabine , Brueck Juergen , Becker Christian , Enk Alexander H.
Published: September 2005

Anti (α)-DEC-205 antibodies target to the DEC-205 receptor that mediates antigen presentation to T cells by dendritic cells. To exploit these properties for immunization purposes, we conjugated the melanoma antigen tyrosinase-related protein (TRP)-2 to αDEC-205 antibodies and immunized mice with these conjugates together with dendritic cell–activating oligonucleotides (CpG). Upon injection of the melanoma cell line B16, αDEC-TRP immunized mice were protected against tumor growth. Even more important for clinical applications, we were able to substantially slow the growth of implanted B16 cells by injection of αDEC-TRP2 conjugates into tumor bearing hosts. Approximately 70% of the animals were cured from existing tumors by treatment with αDEC conjugates carrying two different melanoma antigens (TRP-2 and gp100). This protection was due to induction of melanoma-specific CD4 and CD8 responses. Thus, these data show that targeting of dendritic cells in situ by the means of antibody-antigen conjugates may be a novel way to induce long-lasting antitumor immunity.
Trafficking of Nuclear Heparin-Binding Epidermal Growth Factor–like Growth Factor into an Epidermal Growth Factor Receptor–Dependent Autocrine Loop in Response to Oxidative Stress
Authors: Kim Jayoung , Adam Rosalyn M. , Freeman Michael R.
Published: September 2005

Heparin-binding epidermal growth factor (EGF)–like growth factor (HB-EGF) accumulates in the nucleus in aggressive transitional cell carcinoma (TCC) cells and this histologic feature is a marker of poor prognosis in human bladder cancer tissues. Here we report that HB-EGF can be exported from the nucleus during stimulated processing and secretion of the growth factor. Production of reactive oxygen species (ROS) resulted in mobilization of the HB-EGF precursor, proHB-EGF, from the nucleus of TCCSUP bladder cancer cells to a detergent-resistant membrane compartment, where the growth factor was cleaved by a metalloproteinase-mediated mechanism and shed into the extracellular space. Inhibition of nuclear export suppressed HB-EGF shedding. Production of ROS resulted in EGF receptor (EGFR) and Akt1 phosphorylation in HB-EGF–expressing cells. HB-EGF also stimulated cell proliferation and conferred cytoprotection when cells were challenged with cisplatin. These findings show that the nucleus can serve as an intracellular reservoir for a secreted EGFR ligand and, thus, can contribute to an autocrine loop leading to cell proliferation and protection from apoptotic stimuli.
Expression and Targeting of Interleukin-4 Receptor for Primary and Advanced Ovarian Cancer Therapy
Authors: Kioi Mitomu , Takahashi Satoru , Kawakami Mariko , Kawakami Koji , Kreitman Robert J. , Puri Raj K.
Published: September 2005

Because the most characteristic property of ovarian cancer is i.p. spread, the majority of patients are diagnosed at an advanced stage, leading to limited availability of options for curative therapies. With an intent to identify targeted therapeutic approaches, we have observed that ∼60% of 21 ovarian cancer tissue samples express a high density of interleukin-4 receptor (IL-4R), whereas normal ovarian tissues tested (n = 7) expressed no or low levels of IL-4R. To target IL-4R, we have developed IL-4 cytotoxin, in which circular-permuted IL-4 is fused to a mutated form of Pseudomonas exotoxin. This cytotoxin is specifically and highly cytotoxic to PA-1, IGROV-1, and SK-OV3 ovarian carcinoma cell lines in vitro. In addition, it shows remarkable antitumor activities against established s.c. ovarian tumors in immunodeficient animals. i.p. administration of IL-4 cytotoxin in mice with orthotopically implanted ovarian tumors caused regression of established tumors and prevented these animals from tumor metastasis. Continuous i.p. infusion of IL-4 cytotoxin prolonged survival of tumor-bearing mice even with bulky disease. These results indicate that IL-4R–targeted cytotoxin may be a useful agent for the management of patients with ovarian cancer, and further studies need to be done to evaluate its safety, tolerability, and efficacy.
WW Domain–Containing Proteins, WWOX and YAP, Compete for Interaction with ErbB-4 and Modulate Its Transcriptional Function
Authors: Aqeilan Rami I. , Donati Valentina , Palamarchuk Alexey , Trapasso Francesco , Kaou Mohamed , Pekarsky Yuri , Sudol Marius , Croce Carlo M.
Published: September 2005

The WW domain–containing oxidoreductase, WWOX, is a tumor suppressor that is deleted or altered in several cancer types. We recently showed that WWOX interacts with p73 and AP-2γ and suppresses their transcriptional activity. Yes-associated protein (YAP), also containing WW domains, was shown to associate with p73 and enhance its transcriptional activity. In addition, YAP interacts with ErbB-4 receptor tyrosine kinase and acts as transcriptional coactivator of the COOH-terminal fragment (CTF) of ErbB-4. Stimulation of ErbB-4–expressing cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) results in the proteolytic cleavage of its cytoplasmic domain and translocation of this domain to the nucleus. Here we report that WWOX physically associates with the full-length ErbB-4 via its first WW domain. Coexpression of WWOX and ErbB-4 in HeLa cells followed by treatment with TPA results in the retention of ErbB-4 in the cytoplasm. Moreover, in MCF-7 breast carcinoma cells, expressing high levels of endogenous WWOX, endogenous ErbB-4 is also retained in the cytoplasm. In addition, our results show that interaction of WWOX and ErbB-4 suppresses transcriptional coactivation of CTF by YAP in a dose-dependent manner. A mutant form of WWOX lacking interaction with ErbB-4 has no effect on this coactivation of ErbB-4. Furthermore, WWOX is able to inhibit coactivation of p73 by YAP. In summary, our data indicate that WWOX antagonizes the function of YAP by competing for interaction with ErbB-4 and other targets and thus affect its transcriptional activity.
Resistance to Paclitaxel Is Proportional to Cellular Total Antioxidant Capacity
Authors: Ramanathan Balakrishnan , Jan Kun-Yan , Chen Chien-Hung , Hour Tzyh-Chyuan , Yu Hong-Jen , Pu Yeong-Shiau
Published: September 2005

Paclitaxel, one of the most commonly prescribed chemotherapeutic agents, is active against a wide spectrum of human cancer. The mechanism of its cytotoxicity, however, remains controversial. Our results indicate that paclitaxel treatment increases levels of superoxide, hydrogen peroxide, nitric oxide (NO), oxidative DNA adducts, G2-M arrest, and cells with fragmented nuclei. Antioxidants pyruvate and selenium, the NO synthase inhibitor Nω-nitro-l-arginine methyl ester, and the NO scavenger manganese (III) 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide all decreased paclitaxel-mediated DNA damage and sub-G1 cells. In contrast, the glutamylcysteine synthase inhibitor buthionine sulfoximine (BSO) and the superoxide dismutase (SOD) inhibitor 2-methoxyestradiol (2-ME) increased the sub-G1 fraction in paclitaxel-treated cells. These results suggest that reactive oxygen and nitrogen species are involved in paclitaxel cytotoxicity. This notion is further supported with the observation that concentrations of paclitaxel required to inhibit cell growth by 50% correlate with total antioxidant capacity. Moreover, agents such as arsenic trioxide (As2O3), BSO, 2-ME, PD98059, U0126 [mitogen-activated protein/extracellular signal-regulated kinase inhibitors], and LY294002 (phosphatidylinositol 3-kinase/Akt inhibitor), all of which decrease clonogenic survival, also decrease the total antioxidant capacity of paclitaxel-treated cells, regardless whether they are paclitaxel sensitive or paclitaxel resistant. These results suggest that paclitaxel chemosensitivity may be predicted by taking total antioxidant capacity measurements from clinical tumor samples. This, in turn, may then improve treatment outcomes by selecting out potentially responsive patients.
Mammalian Sterile 20–Like Kinases in Tumor Suppression: An Emerging Pathway
Authors: O'Neill Eric E. , Matallanas David , Kolch Walter
Published: September 2005

Emerging evidence suggests that the proapoptotic kinase mammalian sterile 20–like kinase 2 (MST2) acts in a novel tumor suppression pathway. Recently, we showed that Raf-1 kinase sequesters and inhibits MST2 and that this event is critical for Raf-mediated cell survival. In this review, we summarize Raf control of MST2 and we outline a novel pathway involving the downstream effector proteins Salvador and Warts/Lats that may act to limit the positive effects of Raf–mitogen-activated protein kinase signaling in cancer cells.
Intrathecal Administration of Y-27632, a Specific Rho-Associated Kinase Inhibitor, for Rat Neoplastic Meningitis
Authors: Nakagawa Hidemitsu , Yoshioka Kiyoko , Miyahara Eiji , Fukushima Yuji , Tamura Masakazu , Itoh Kazuyuki
Published: September 2005

The small GTP-binding protein Rho and its target Rho-associated kinase trigger an intracellular signaling cascade that controls actin cytoskeleton and plays an essential role in cell motility and adhesion. A specific Rho-associated kinase inhibitor, Y-27632, has been reported to inhibit cancer invasion. Clinically, disseminated tumor cells in the cerebrospinal fluid invade the intraparenchymal region, damaging the brain and nerves, resulting in fatal brain stem dysfunction, despite intrathecal chemotherapy. To expand therapeutic options for this devastating neoplastic meningitis, we evaluated the potential use of intrathecal Y-27632 administration by employing Walker 256 cells, a rat mammary cancer cell line. Y-27632 dose-dependently inhibited chemotactic and invasive activity of Walker 256 cells. Y-27632 also inhibited the phosphorylation level of regulatory myosin light chain in vitro, but the effect was temporary and was considerably diminished within 16 hours. Y-27632 induced striking morphologic changes in Walker 256 cells, as evidenced by decreased cell-matrix adhesion in culture dishes and three-dimensional collagen I gels, and slightly inhibited colony formation in soft agar. Nevertheless, this drug treatment did not affect Walker 256 cell growth rate. We were able to administer continuous delivery of this inhibitor using an osmotic pump and maintaining drug concentration of 10 μmol/L within the brain. Importantly, this concentration of Y-27632 showed minimal neurotoxicity both in vitro and in vivo. We found that an intrathecal therapy, combining 5-fluoro-2′-deoxyuridine with Y-27632, significantly increased the survival time of rats bearing meningeal carcinomatosis in comparison with animals treated with 5-fluoro-2′-deoxyuridine alone. Taken together, our findings indicate that continuous intrathecal administration of Y-27632 could be a promising therapeutic method when combined with chemotherapy for treating human neoplastic meningitis.
Endothelial/Pericyte Interactions
Authors: Armulik Annika , Abramsson Alexandra , Betsholtz Christer
Published: September 2005

Interactions between endothelial cells and mural cells (pericytes and vascular smooth muscle cells) in the blood vessel wall have recently come into focus as central processes in the regulation of vascular formation, stabilization, remodeling, and function. Failure of the interactions between the 2 cell types, as seen in numerous genetic mouse models, results in severe and often lethal cardiovascular defects. Abnormal interactions between the 2 cell types are also implicated in a number of human pathological conditions, including tumor angiogenesis, diabetic microangiopathy, ectopic tissue calcification, and stroke and dementia syndrome CADASIL. In the present review, we summarize current knowledge concerning the identity, characteristics, diversity, ontogeny, and plasticity of pericytes. We focus on the advancement in recent years of the understanding of intercellular communication between endothelial and mural cells with a focus on transforming growth factor β, angiopoietins, platelet-derived growth factor, spingosine-1-phosphate, and Notch ligands and their respective receptors. We finally highlight recent important data contributing to the understanding of the role of pericytes in tumor angiogenesis, diabetic retinopathy, and hereditary lymphedema.
Learning and Transfer of an Ipsilateral Coordination Task: Evidence for a Dual-layer Movement Representation
Authors: Vangheluwe Sophie , Wenderoth Nicole , Swinnen Stephan P.
Published: September 2005

The present study addressed the nature of the memory representation for interlimb coordination tasks. For this purpose, the acquisition of a multifrequency (2:1) task with the ipsilateral limbs and transfer to the ipsilateral and contralateral body side was examined. In particular, subjects practiced a 2:1 coordination pattern whereby the right arm moved twice as fast as the right leg, or vice versa. Subsequently, they transferred the practiced 2:1 task to three different conditions: (1) the converse partner (i.e., the slow-moving limb had to move fast, and vice versa) at the ipsilateral body side, and (2) the identical and (3) converse 2:1 pattern at the contralateral body side. Findings revealed positive transfer of the identical and converse 2:1 pattern to the contralateral body side. However, no transfer of the learned pattern to its converse partner at the same body side was revealed. We propose a new memory representation model for coordination patterns, composed of an effector-independent and effector-specific component (dual-layer model). It is hypothesized that the general movement goal (i.e., moving one limb twice as fast as the other) constitutes the abstract, higher-level representation that may account for positive contralateral transfer. Conversely, the effector-specific component contains task-specific lower-level muscle synergies that are acquired through practice, prohibiting positive transfer when shifting task allocation within the same effectors. These findings are consistent with recent neuroscientific evidence for neuroplastic changes in distributed brain areas.
The Neurophysiology of Functionally Meaningful Categories: Macaque Ventrolateral Prefrontal Cortex Plays a Critical Role in Spontaneous Categorization of Species-Specific Vocalizations
Authors: Gifford Gordon W. , MacLean Katherine A. , Hauser Marc D. , Cohen Yale E.
Published: September 2005

Neurophysiological studies in nonhuman primates have demonstrated that the prefrontal cortex (PFC) plays a critical role in the acquisition of learned categories following training. What is presently unclear is whether this cortical area also plays a role in spontaneous recognition and discrimination of natural categories. Here, we explore this possibility by recording from neurons in the PFC while rhesus listen to species-specific vocalizations that vary in terms of their social function and acoustic morphology. We found that ventral prefrontal cortex (vPFC) activity, on average, did not differentiate between food calls that were associated with the same functional category, despite having different acoustic properties. In contrast, vPFC activity differentiated between food calls associated with different functional classes and specifically, information about the quality and motivational value of the food. These results suggest that the vPFC is involved in the categorization of socially meaningful signals, thereby both extending its previously conceived role in the acquisition of learned categories and showing the significance of using natural categorical distinctions in the study of neural mechanisms.
Different Brain Strategies Underlie the Categorical Perception of Foreign and Native Phonemes
Authors: Minagawa-Kawai Yasuyo , Mori Koichi , Sato Yutaka
Published: September 2005

The present study using near-infrared spectroscopy examined the neuronal correlates of Japanese long/short vowel contrast discrimination and its relationship with behavioral performance by comparing native Japanese (L1) subjects and Korean subjects learning Japanese as a second language (L2). Phoneme-specific responses were predominantly observed in the left auditory area only in the L1 subjects, although the behavioral scores of the L2 subjects indicated categorical perception (CP) that was indistinguishable from that of the L1 subjects. These inconsistent relationships were more evident in the correlation coefficients between the brain recording and behavior. However, slower reaction times and non-specific brain responses in the L2 listeners suggest differences in their cortical processes from those of the L1 subjects. These findings suggest that the CP of L2 phonemes as determined by behavioral scores alone does not always predict a language-specific neural processing as employed by the L1 listeners.
ZnS-Epoxy Resin Nanocomposite Prepared by a Novel Method
Authors: Yiyun Cheng , Pingsheng He , Dazhu Chen , Ronghui Cui
Published: September 2005

This study presents a new method to prepare the ZnS-epoxy resin nanocomposites. An epoxy resin microemulsion is taken as a microreactor for the formation of ZnS nanocrystals. After the reaction, the collected epoxy resin is proved to be a composite with embedded nanoZnS. X-ray diffraction (XRD) and transmission electron microscopy (TEM) indicated that the ZnS nanocrystals are dispersed uniformly in cured epoxy resin matrix.
Levetiracetam in social phobia: a placebo controlled pilot study
Authors: Zhang Wei , Connor Kathryn M. , Davidson Jonathan R. T.
Published: September 2005

While serotonergic antidepressants are now established as first-line pharamcotherapy for generalized social anxiety disorder (SAD), other agents with different mechanisms have shown promise in treating SAD. The aim of this pilot study is to examine the efficacy and safety of levetiracetam (LEV), an anticonvulsant with calcium channel modulating properties, in treating SAD. Adult outpatients meeting DSM-IV criteria for SAD were randomly assigned (2:1) to double-blind treatment with either LEV (500-3000mg/day) or placebo (PBO) for 7 weeks. The primary outcome measures were the change from baseline in the Brief Social Phobia Scale (BSPS) and response using the Clinical Global Impression of Improvement scale (CGI-I). The mean (SD) BSPS scores at baseline and endpoint were 45.4 (9.7) and 31.2 (19.7) for LEV (n 9), compared to 43.5 (8.4) and 37.8 (19.9) for PBO (n 7) (ITT; ns). Rates of response were 22% for LEV and 14% for PBO using the CGI-I. Using a BSPS response criterion (>30% reduction), response rates were 44% for LEV and 14% for PBO. The effect sizes of LEV relative to PBO were 0.33 for the BSPS and 0.50 for the LSAS. In summary, the results of this study, while negative on the pre-defined measures, suggest promise for LEV as a new treatment of SAD. Further work should be carried out with larger sample sizes and optimal dosing strategies of the drug.
Understanding Interpersonal Trust in a Confucian-influenced Society
Authors: Tan Hwee Hoon , Chee Dave
Published: September 2005

Adopting a qualitative methodology, this exploratory study examined the construct of trust and its factors of trustworthiness as perceived in a Confucian-influenced society. The findings of our study indicated that there are emic differences in the meaning of trust as perceived in a Confucian-influenced setting. Specifically, we found a heavy reliance on affective factors of trustworthiness in the decision to trust. In addition, we found a number of factors unique to the context that facilitates the development of trust: diligence, perseverance, filial piety, thriftiness, respect for authority, a shared value of collective effort, harmonious relationship in the office, humbleness and magnanimous behavior. Implications are drawn and future research directions suggested.
Promotion Criteria and Satisfaction of School Teachers in Hong Kong
Authors: Wong Ping-Man , Wong Chi-Sum
Published: September 2005

Teacher promotion is an important issue in school administration that deserves more academic attention. In business management a commonly used tool for employee motivation, aside from promotion, is the compensation system, which can be flexibly and frequently adjusted with the performance of individual staff members. However, in the existing education system, pay levels and structure are relatively fixed and it is difficult for principals to use the compensation system as a tool to motivate teachers. Promotion is therefore the most important reward that principals can use. Using Hong Kong as an example, and with a sample of 210 principals and teachers from both primary and secondary schools, this article attempts to find answers and make suggestions to improve the current promotion system. It is hoped that this study will provide a better understanding of teacher promotion in general, and in Hong Kong in particular.
Effects of type and level of training on variation in physician knowledge in the use and acquisition of blood cultures: a cross sectional survey
Authors: Parada Jorge P , Schwartz David N , Schiff Gordon D , Weiss Kevin B
Published: September 2005

Background

Blood culture (BCX) use is often sub-optimal, and is a user-dependent diagnostic test. Little is known about physician training and BCX-related knowledge. We sought to assess variations in caregiver BCX-related knowledge, and their relation to medical training.

Methods

We developed and piloted a self-administered BCX-related knowledge survey instrument. Expert opinion, literature review, focus groups, and mini-pilots reduced > 100 questions in multiple formats to a final questionnaire with 15 scored content items and 4 covariate identifiers. This questionnaire was used in a cross-sectional survey of physicians, fellows, residents and medical students at a large urban public teaching hospital. The responses were stratified by years/level of training, type of specialty training, self-reported practical and theoretical BCX-related instruction. Summary scores were derived from participant responses compared to a 95% consensus opinion of infectious diseases specialists that matched an evidence based reference standard.

Results

There were 291 respondents (Attendings = 72, Post-Graduate Year (PGY) = 3 = 84, PGY2 = 42, PGY1 = 41, medical students = 52). Mean scores differed by training level (Attending = 85.0, PGY3 = 81.1, PGY2 = 78.4, PGY1 = 75.4, students = 67.7) [p ≤ 0.001], and training type (Infectious Diseases = 96.1, Medicine = 81.7, Emergency Medicine = 79.6, Surgery = 78.5, Family Practice = 76.5, Obstetrics-Gynecology = 74.4, Pediatrics = 74.0) [p ≤ 0.001]. Higher summary scores were associated with self-reported theoretical [p ≤ 0.001] and practical [p = 0.001] BCX-related training. Linear regression showed level and type of training accounted for most of the score variation.

Conclusion

Higher mean scores were associated with advancing level of training and greater subject-related training. Notably, house staff and medical students, who are most likely to order and/or obtain BCXs, lack key BCX-related knowledge. Targeted education may improve utilization of this important diagnostic tool.
Giant cell tumor of the temporal bone – a case report
Authors: Pai S Balaji , Lalitha RM , Prasad Kavitha , Rao Saraswathi G , Harish K
Published: September 2005

Background

Giant cell tumor is a benign but locally aggressive bone neoplasm which uncommonly involves the skull. The petrous portion of the temporal bone forms a rare location for this tumor.

Case presentation

The authors report a case of a large giant cell tumor involving the petrous and squamous portions of the temporal bone in a 26 year old male patient. He presented with right side severe hearing loss and facial paresis. Radical excision of the tumor was achieved but facial palsy could not be avoided.

Conclusion

Radical excision of skull base giant cell tumor may be hazardous but if achieved is the optimal treatment and may be curative.
Doctor-patient interaction in Finnish primary health care as perceived by first year medical students
Authors: Miettola Juhani , Mäntyselkä Pekka , Vaskilampi Tuula
Published: September 2005

Background

In Finland, public health care is the responsibility of primary health care centres, which render a wide range of community level preventive, curative and rehabilitative medical care. Since 1990's, medical studies have involved early familiarization of medical students with general practice from the beginning of the studies, as this pre-clinical familiarisation helps medical students understand patients as human beings, recognise the importance of the doctor-patient relationship and identify practicing general practitioners (GPs) as role models for their professional development. Focused on doctor-patient relationship, we analysed the reports of 2002 first year medical students in the University of Kuopio. The students observed GPs' work during their 2-day visit to primary health care centres.

Methods

We analysed systematically the texts of 127 written reports of 2002, which represents 95.5% of the 133 first year pre-clinical medical students reports. The reports of 2003 (N = 118) and 2004 (N = 130) were used as reference material.

Results

Majority of the students reported GPs as positive role models. Some students reported GPs' poor attitudes, which they, however, regarded as a learning opportunity. Students generally observed a great variety of responsibilities in general practice, and expressed admiration for the skills and abilities required. They appreciated the GPs' interest in patients concerns. GPs' communication styles were found to vary considerably. Students reported some factors disturbing the consultation session, such as the GP staring at the computer screen and other team members entering the room. Working with marginalized groups, the chronically and terminally ill, and dying patients was seen as an area for development in the busy Finnish primary health care centres.

Conclusion

During the analysis, we discovered that medical students' perceptions in this study are in line with the previous findings about the importance of role model (good or bad) in making good doctors. Therefore, medical students' pre-clinical primary health care centre visits may influence their attitudes towards primary health care work and the doctor-patient relationship. We welcome more European studies on the role of early pre-clinical general practice exposure on medical students' primary care specialty choice.
Sequence and structural analysis of BTB domain proteins
Authors: Stogios Peter J , Downs Gregory S , Jauhal Jimmy JS , Nandra Sukhjeen K , Privé Gilbert G
Published: September 2005

Background

The BTB domain (also known as the POZ domain) is a versatile protein-protein interaction motif that participates in a wide range of cellular functions, including transcriptional regulation, cytoskeleton dynamics, ion channel assembly and gating, and targeting proteins for ubiquitination. Several BTB domain structures have been experimentally determined, revealing a highly conserved core structure.

Results

We surveyed the protein architecture, genomic distribution and sequence conservation of BTB domain proteins in 17 fully sequenced eukaryotes. The BTB domain is typically found as a single copy in proteins that contain only one or two other types of domain, and this defines the BTB-zinc finger (BTB-ZF), BTB-BACK-kelch (BBK), voltage-gated potassium channel T1 (T1-Kv), MATH-BTB, BTB-NPH3 and BTB-BACK-PHR (BBP) families of proteins, among others. In contrast, the Skp1 and ElonginC proteins consist almost exclusively of the core BTB fold. There are numerous lineage-specific expansions of BTB proteins, as seen by the relatively large number of BTB-ZF and BBK proteins in vertebrates, MATH-BTB proteins in Caenorhabditis elegans, and BTB-NPH3 proteins in Arabidopsis thaliana. Using the structural homology between Skp1 and the PLZF BTB homodimer, we present a model of a BTB-Cul3 SCF-like E3 ubiquitin ligase complex that shows that the BTB dimer or the T1 tetramer is compatible in this complex.

Conclusion

Despite widely divergent sequences, the BTB fold is structurally well conserved. The fold has adapted to several different modes of self-association and interactions with non-BTB proteins.
Teachers’ knowledge and experience in the discourse of foreign-language classrooms
Authors: Lacorte Manel
Published: September 2005

Recent research on second language acquisition (SLA) has strengthened foreign (FL) and second language (L2) teaching methodologies supporting the development of communicative tasks, interactive activities in the classroom, and learner-centred instruction. However, these and any other trends in FL and L2 teaching and learning could be more beneficial if teachers and teacher educators would deepen their understanding of the diverse pedagogical and institutional conditions that may influence classroom work. As part of a wider interest in the relationship between teachers’ knowledge and beliefs and their practices in a number of classrooms of Spanish in the USA, this qualitative study focuses on the teachers’ management of the transitions between instructional stages - i.e., phases in the development of a lesson - with specific attention to the analysis of interaction and control during the transitions.
Exploratory Practice and Soft Systems Methodology
Authors: Tajino Akira , Smith Craig
Published: September 2005

This paper aims to demonstrate that Soft Systems Methodology (SSM), a soft systems approach developed in management studies (see Checkland, 1981), can be usefully linked with Exploratory Practice (EP), a form of practitioner research for language classrooms. Some compatible SSM and EP characteristics, in tandem, could enhance continual efforts to develop better understandings among teachers and learners of what they are doing together. An application of SSM communication-facilitating systems to EP is discussed. Unlike typical ‘hard’ systems approaches which have been developed in natural sciences to solve problems involving clear cause-effect relationships, SSM is a ‘soft’ systems approach that deals with complex human situations in which people with various world views, or senses of values, are engaged in communication. We argue that SSM can help EP practitioners deepen their understandings of language learning and life in language classrooms, and help develop their potential as learners and teachers.
Thermodynamics of Light‐induced and Thermal Degradation of Bacteriochlorins in Reaction Center Protein of Photosynthetic Bacteria
Authors: Tandori Júlia , Tokaji Zsolt , Misurda Katalin , Maróti Péter
Published: September 2005

The rate constants of thermal (irreversible) damage of bacteriochlorin pigments (bacteriochlorophyll monomer [B], bacteriochlorophyll dimer [P] and bacteriopheophytine [H]) in reaction center [RC] protein from the photosynthetic bacterium Rhodobacter sphaeroides were studied in the dark and during intense (400 mW · cm−2) laser light excitation (wavelengths 488 and 515 nm) under deoxygenated conditions. While the kinetics of degradation of P and B were monoexponential, the decay kinetics of H were overlapped by an initial lag phase at elevated (> 40°C) temperature. This is explained by removal of the central metal ion from the bacteriochlorophylls as part of their degradation processes. At all temperatures, the rates of damage were very similar for all bacteriochlorin pigments and were larger in the light than in the dark. The logarithm of the rate constant of pigment degradation and loss of photochemistry as a function of reciprocal (absolute) temperature (Arrhenius/Esyring plot) showed single phase in the light and double phases in the dark. Below 20°C, the rate of pigment degradation in the RC decreased so dramatically in the dark that it became limited by the natural degradation process of bacteriochlorophyll measured in solution. The function of loss of photochemistry in the dark was also biphasic and had a break point at 40°C. The damage in the dark required high enthalpy change (ΔH‡= 64 kcal/mol for P and ΔH‡= 60 kcal/mol for B) and entropy increase (T·ΔS‡= 38 kcal/mol for P and T·ΔS‡= 34 kcal/mol for B at T= 300 K), whereas significantly smaller enthalpy change (ΔH‡= 21 kcal/mol for P and B and ΔH‡= 13 kcal/mol for H) and practically no (T·ΔS‡=−1 kcal/mol for P and B at T= 300 K) or small (T·ΔS‡=−9 kcal/mol for H at T= 300 K) entropy change was needed in the light. The thermodynamic parameters of activation reveal major steps common in the degradation of all bacteriochlorin pigments: ring opening reactions at C5 or C20 meso‐bridges (or both) and breaking/removal of the phytyl chain. Their contribution in the degradation is probably reflected in the observed enthalpy/entropy compensation at an almost constant (ΔG‡= 22–26 kcal/mol at T= 300 K) free energy change of activation.
Photochemistry and Photobiology of Cryptochrome Blue‐light Photopigments: The Search for a Photocycle
Authors: Partch Carrie L. , Sancar Aziz
Published: September 2005

Cryptochromes are flavoproteins that exhibit high sequence and structural similarity to the light‐dependent DNA‐repair enzyme, photolyase. Cryptochromes have lost the ability to repair DNA; instead, they use the energy from near‐UV/blue light to regulate a variety of growth and adaptive processes in organisms ranging from bacteria to humans. The photocycle of cryptochrome is not yet known, although it is hypothesized that it may share some similarity to that of photolyase, which utilizes light‐driven electron transfer from the catalytic flavin chromophore. In this review, we present genetic evidence for the photoreceptive role of cryptochromes and discuss recent biochemical studies that have furthered our understanding of the cryptochrome photocycle. In particular, the role of the unique C‐terminal domain in cryptochrome phototransduction is discussed.
Copolymerization of N‐(4‐carboxyphenyl) itaconimide or N‐(4‐carboxyphenyl) itaconamic acid with methyl methacrylate
Authors: Chauhan Rashmi , Choudhary Veena
Published: September 2005

This paper describes the synthesis and characterization of N‐(4‐carboxyphenyl) itaconamic acid (CPA) and N‐(4‐carboxyphenyl) itaconimide (CPI) obtained by reacting itaconic anhydride with p‐aminobenzoic acid. Structural and thermal characterization of CPA and CPI was done using 1H‐NMR, FTIR, and differential scanning calorimetry (DSC). Copolymerization of CPA or CPI with methyl methacrylate (MMA) in solution was carried out at 60 °C using azobisisobutyronitrile as an initiator and dimethyl acetamide or THF as solvent. Feed compositions having varying mole fractions of CPA or CPI ranging from 0.05–0.20 or 0.1–0.5 were taken to prepare copolymers. Copolymerizations were terminated at low percentage conversion. Structural characterization of copolymers was done by 1H‐NMR and elemental analysis. Copolymer composition was determined using percentage nitrogen content. The reactivity ratios were r1 (MMA) = 0.68 ± 0.06 and r2 (CPI) = 0.46 ± 0.06. The intrinsic viscosity [η] was determined using an Ubbelohde suspension level viscometer. [η] decreased with increasing mole fraction of N‐(p‐carboxyphenyl) itaconimide or N‐(p‐carboxyphenyl) itaconamic acid in copolymers. Glass transition temperature and thermal stability of the copolymers were determined using DSC and thermogravimetric analysis, respectively. The glass transition temperature (Tg) as determined from DSC scans increased with increasing amounts of CPA or CPI in copolymers. A significant improvement in the char yield was observed upon copolymerization. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 1909–1915, 2005
Studies on miscibility of blends of poly (ethylene acrylic acid) and ethylene‐co‐vinyl acetate by melt rheology
Authors: Siddaramaiah  , Bhattacharya A. K. , Nando G. B.
Published: September 2005

Rheological behavior of blends of poly (ethylene‐acrylic acid) (EAA) and ethylene vinyl acetate (EVA) copolymer have been carried out at various temperatures, namely, 100, 110, and 120°C, and different shear rates from 61.33 to 613.30 s−1 using a Monsanto Processability Tester. The melt viscosity of the blends shows synergism during processing. The activation energy of the blends is in the range 20.7–44.6 kJ/mol. Highest activation energy was observed for the blends containing 40–60% of EVA by weight. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 1947–1954, 2005