bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

AbstractThe 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.
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

Abstract
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

Abstract
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

Abstract
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.
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

Abstract

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

Abstract

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

Abstract

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

Abstract
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.
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

ABSTRACTThe 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.