bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational screening of branched cyclic peptide motifs as potential enzyme mimetics
Authors: Stavrakoudis Athanassios , Makropoulou Sevasti , Tsikaris Vassilios , Sakarellos‐Daitsiotis Maria , Sakarellos Constantinos , Demetropoulos Ioannis N. 
Published: March 2003

AbstractIn a previous work we described the design, synthesis and catalytic activity of a branched cyclic peptide as a serine protease mimic. To maximize its catalytic activity we present now a systematic search of a large number of homologous peptides for potential enzyme activity as revealed by the topological arrangement of the catalytic triad residues. This process is accomplished by applying a combined molecular mechanics and molecular dynamics conformational search of about 200 molecules. Starting from a previously synthesized compound that showed some hydrolytic activity several analogues were modelled by amino acid substitutions in the main molecular framework using the Insight II molecular modelling environment with some script automation. Also presented is an algorithm that: (a) generates all possible combinations of residue substitutions, (b) scans the conformational space for each molecule via high temperature molecular dynamics, (c) picks the set of molecules the trajectories of which retained, to a considerable degree, the catalytic triad molecular arrangement, (d) subjects the selected molecules to layer solvation and energy minimization and chooses the molecules, the conformations of which could preserve the catalytic triad arrangement. Finally, a modelling with periodic boundary conditions, was performed to further support the reported algorithm. We found that at least one of the analogues could be a potential serine protease mimic, as revealed by the root‐mean‐square comparison between the catalytic triad in two molecular dynamics trajectories of the peptide and the corresponding residues in the crystal structure of trypsin. The most promising model candidate was synthesized and tested for its catalytic activity. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.
Effect of pH on the aggregate formation of a non‐amyloid component (1–13)
Authors: Abe Hiroshi , Nakanishi Hiroshi 
Published: March 2003

AbstractThe formation of aggregates including amyloid fibrils in the peptide fragment of non‐amyloid‐β component (NAC(1–13)) was investigated under a variety of solution conditions. Two types of sample preparation method from neutral and acidic conditions were examined. Electron microscopy observation showed amorphous aggregates in the sample at pH 4.5 adjusted from the neutral condition. The CD and HPLC quantitative analyses indicated that the formation of the amorphous aggregate did not accompany a conformational conversion from a random coil in the sample solution. The analyses of pKa values determined by pH titration experiments in NMR spectroscopy indicated that the protonation of the carboxyl group of the N‐terminal glutamic acid triggers the aggregation of NAC(1–13). On the other hand, electron microscopy observation showed that the samples at pH 2.2 and 4.5 adjusted from an initial pH of 2.2 form fibrils. A β‐structure was detected by CD spectroscopy in the 1 mM NAC(1–13) at pH 2.2 immediately after preparation. The CD analyses of samples at different concentrations and temperatures indicated that 1 mM NAC(1–13) immediately after preparation at pH 2.2 was oligomerized. The quantity of the β‐structure was increased depending on the incubation time. The results strongly suggested that the β‐conformational oligomers play a critical role for the fibril nucleus. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.
Spontaneous and experimental osteoarthritis in dog: Similarities and differences in proteoglycan levels
Authors: Liu Wenhua , Burton‐Wurster Nancy , Glant Tibor T. , Tashman Scott , Sumner Dale R. , Kamath Rajesh V. , Lust George , Kimura James H. , Cs‐Szabo Gabriella 
Published: March 2003

AbstractThe unilateral canine model is the most commonly used model of experimental osteoarthritis (OA). In this model, the anterior cruciate ligament (ACL) of one knee is transected and the contralateral joint is usually used as a control. However, dogs, similar to humans, can develop OA spontaneously with old age. Additionally, certain breeds of dogs are genetically predisposed to OA and can develop symptoms at a young age. The goal of this study was to compare the pathological changes of proteoglycans in OA cartilage from dogs that developed OA spontaneously to those that underwent ACL transection. For this reason, biglycan, decorin and fibromodulin levels and degradation patterns were compared by Western blot hybridization, and aggrecan contents were quantified by dimethylmethylene blue assay. The changes in proteoglycan levels in the cartilage of dogs with spontaneous OA, regardless of their age, were very similar to those published for human OA cartilage. However, when OA developed as a result of ACL‐surgery, the changes in proteoglycans were different from those of slowly developing spontaneous OA. Therefore, these differences should be taken into consideration when the ACL‐transection model is used. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Maple syrup urine disease: Mutation analysis in Turkish patients
Authors: Dursun A. , Henneke M. , Özgül K. , Gartner J. , Coşkun T. , Tokatli A. , Kalkanoğlu H. S. , Demirkol M. , Wendel U. , Özalp İ. 
Published: March 2003

AbstractMaple syrup urine disease (MSUD), the most frequently occurring organic acidaemia in Turkey, is caused by a deficiency of the activity of branched‐chain keto acid dehydrogenase enzyme (BCKAD) complex. Mutation analysis of the E1α, E1β, and E2 genes of the BCKAD complex in 12 Turkish MSUD patients yielded three disease‐specific mutations and a polymorphism in the E1α gene, none in the E1β gene and one mutation in the E2 gene. Among them, three missense mutations (Q80E, C213Y, T106M) and the F280F polymorphism occurring in the E1α gene and the splice site mutation (IVS3 − 1G > A) in the E2 gene were novel. Three of the missense mutations and the splicing mutation occurred homozygously and caused classical MSUD. One patient carried the splicing mutation homozygously and the T106M mutation in the heterozygous state; this patient is the first case having simultaneously two different mutations in two different genes in the BCKAD complex. IVS3 − 1G > A splicing mutation detected on the E2 gene causes deletion of the first 14 bp of exon 3 in the mutant mRNA extending between 190 and 204 nt. The deletion spans the cleavage point between mitochondrial targeting and lipoyl‐bearing site of the E2 protein.
Towards a New Role for Occupational Pensions in Continental Europe: Elements and Techniques of Solidarity Used within Funded Occupational Pension Schemes
Authors: Stevens Yves , Gieselink Gerhard , Van Buggenhout Bea 
Published: March 2003

‘At first glance, it may seem incongruous to talk of private pensions in terms of equity. We do not for example, question whether champagne consumption is fairly distributed.’ This paper is about the debate on occupational pensions in continental Europe. Instead of looking at the financial issues, it looks at the elements of social protection and solidarity within occupational pensions. Occupational pensions are of increasing importance for continental European society. This is indicated by a so-called ‘new pension order’ that is predominantly influenced by the Anglo-Saxon vision of pensions. However, much of the ongoing (legal) debate on pension reform deals with elements such as fairness and redistribution.
A Religion for an Age of Science
Authors: Gillette P. Roger 
Published: March 2003

The period 800–200 B.C.E. has been called an axial period or age because it was a period of major technological and cultural change that led to the development of new worldviews, which in turn called for and led to the emergence of the current major world religious traditions. The world is now in the midst of another period of major global scientific, technological, and cultural change that is leading to the development of a new global worldview. In this worldview, the cosmos is taken to be more like an activity than a thing—more like an emergent complex of interrelated and interactive doing in space–time than a created complex of beings in space and time–and its complexity and space—time scale are understood to be enormously greater than heretofore supposed.These changes in worldview call for changes in theology, religion, and ethics. Most workers in the field of science and religion are heeding this call by attempting to reconcile traditional religious concepts with the new scientific concepts. Others, however, have become convinced that the new worldview differs so radically from the previous ones as to mark a new axial age, which calls for a new, post‐traditional theology, religion, and ethics, with a theos that is more like an activator of doing than a ground of being, and with meaning and purpose achieved more by a quality of doing than a quantity or quality of being.
The “God Module” and the Complexifying Brain
Authors: Rausch Albright Carol 
Published: March 2003

Recent reports of the discovery of a “God module” in the human brain derive from the fact that epileptic seizures in the left temporal lobe are associated with ecstatic feelings sometimes described as an experience of the presence of God. The brain area involved has been described as either (a) the seat of an innate human faculty for experiencing the divine or (b) the seat of religious delusions.In fact, religious experience is extremely various and involves many parts of the brain, including some that are prehuman in their evolutionary history and some that are characteristically human. In the continuing integration of such experiences, spiritual formation takes place. Thus the entire human brain might be described as a “God module.”Such a process is only possible because of the brain's complexity. The human brain is the most complex entity for its size that we know of. As used here, complexity is a specialized term denoting the presence of a web of interlinked and significant connections—the more intricate the web, the more complex the entity. Complex systems develop only in a milieu that provides both lawfulness and freedom, and they tend to be self‐organizing, becoming more complex and more effective as a result of both inward and outward experience. The evidence suggests that both personal growth and spiritual growth are processes of complexification of character, and of the brain itself. This thesis is tested in light of the work of William James and James W. Fowler.
Clocks, God, and Scientific Realism
Authors: Schoen Edward L. 
Published: March 2003

Scientists, both modern and contemporary, commonly try to discern patterns in nature. They also frequently use arguments by analogy to construct an understanding of the natural mechanisms responsible for producing such patterns. For Robert Boyle, the famous clock at Strasbourg provided a perfect paradigm for understanding the connection between these two scientific activities. Unfortunately, it also posed a serious threat to his realistic pretensions. All sorts of internal mechanisms could produce precisely the same movements across the face of a clock. Given God's immense creative capacities, Boyle realized that standard epistemological constraints could never ensure, not even to the least degree of probability, that scientific theories about the unobservable mechanisms of nature were descriptively accurate. Like most moderns, he fortified his epistemology theologically in order to retain his realistic stance. John Locke, however, took counsel from Ecclesiastes to repudiate Boyle's realism, while Samuel Clarke mobilized biblical images to dismiss the clockwork paradigm altogether.A contemporary review of this modern controversy reveals that there is still much to learn from the clock at Strasbourg. Among other things, the realism/antirealism issue is of central importance to understanding today's science, Nancey Murphy's protests notwithstanding. Moreover, the kind of realistic stance that is essential, not only to the truth but to the very intelligibility of certain types of scientific explanation, demands more than the critical realism of Ian Barbour. To be taken seriously, the models used in such contexts must be taken literally.
Human Kallikrein 6 (hK6): A New Potential Serum Biomarker for Diagnosis and Prognosis of Ovarian Carcinoma
Authors: Diamandis Eleftherios P. , Scorilas Andreas , Fracchioli Stefano , van Gramberen Marleen , de Bruijn Henk , Henrik Alfthan , Soosaipillai Antoninus , Grass Linda , Yousef George M. , Stenman Ulf-Hakan , Massobrio Marco , van der Zee Ate GJ , Vergote Ignace , Katsaros Dionyssios 
Published: March 2003

Purpose: The discovery of new ovarian cancer biomarkers that are suitable for early disease diagnosis and prognosis may ultimately lead to improved patient management and outcomes. Patients and Methods: We measured, by immunoassay, human kallikrein 6 (hK6) concentration in serum of 97 apparently healthy women, 141 women with benign abdominal diseases, and 146 women with histologically proven primary ovarian carcinoma. We then calculated the diagnostic sensitivity and specificity of this test and examined the association of serum hK6 concentration with various clinicopathologic variables and patient survival. Results: Serum hK6 concentration between normal and benign disease patients was not different (mean, 2.9 and 3.1 μg/L, respectively). However, hK6 in presurgical serum of ovarian cancer patients was highly elevated (mean, 6.8 μg/L; P < .001). Serum hK6 decreased after surgery (to a mean of 3.9 μg/L) in 68% of patients. The diagnostic sensitivity of serum hK6 at 90% and 95% specificity is 52% and 47%, respectively, in the whole patient population. For early stage disease (stage I or II), sensitivity is approximately 21% to 26%. When combined with CA-125, at 90% specificity, sensitivity increases to 72% (for all patients) and to 42% in stage I or II disease. Serum hK6 concentration correlates moderately with CA-125 and is higher in patients with late-stage, higher-grade disease and in patients with serous histotype. Preoperative serum hK6 concentration is a powerful predictor of disease-free and overall survival in both univariate and multivariate analyses. Conclusions: Serum hK6 concentration seems to be a new biomarker for ovarian carcinoma and may have value for disease diagnosis and prognosis.
Immunotherapy of Advanced Breast Cancer With a Heterophilic Ganglioside (NeuGcGM3) Cancer Vaccine
Authors: Carr Adriana , Rodríguez Edmundo , del Carmen Arango María , Camacho Rolando , Osorio Marta , Gabri Mariano , Carrillo Guido , Valdés Zolidina , Bebelagua Yanín , Pérez Rolando , Fernández Luis Enrique 
Published: March 2003

Purpose: A heterophilic ganglioside cancer vaccine was developed by combining NeuGcGM3 with the outer membrane protein complex of Neisseria meningitidis to form very small size proteoliposomes (VSSP). A phase I clinical trial was performed to determine safety and immunogenicity of this vaccine. Patients and Methods: Stage III to IV breast cancer patients received up to 15 (200 μg) doses of the vaccine by intramuscular injection. The first five doses (induction phase) were given at 2-week intervals, with the remaining treatment (maintenance) administered on a monthly basis. Results: Twenty-one patients, 11 of whom had metastatic disease, were included. Main toxicities included erythema and induration at the injection site, sometimes associated with mild pain, and low-grade fever (World Health Organization grades 1 and 2). All treated patients who completed the induction phase developed anti-NeuGcGM3 antibody titers between 1:1,280 and 1:164,000 immunoglobulin G (IgG), and 1:640 and 1:164,000 IgM. Noteworthy specific IgA antibodies were induced by vaccination in all stage III patients and in three stage IV patients. Serum antibody levels were higher in the stage III patients, with the larger increases observed after week 32. The antiganglioside IgG subclasses were mainly IgG1 and IgG3. Hyperimmune sera increased complement-mediated cytotoxicity versus P3X63 myeloma cells and a marked IgG differential reactivity against human mammary ductal carcinoma samples. Conclusion: NeuGcGM3/VSSP/Montanide ISA 51 is an unusual immunogenic ganglioside vaccine and also seems to be safe in this small trial. Immunologic surrogates of activity indicate that this reagent warrants further investigation.
Phase I Clinical and Pharmacology Study of Clofarabine in Patients With Solid and Hematologic Cancers
Authors: Kantarjian Hagop M. , Gandhi Varsha , Kozuch Peter , Faderl Stefan , Giles Francis , Cortes Jorge , O’Brien Susan , Ibrahim Nuhad , Khuri Fadlo , Du Min , Rios Mary Beth , Jeha Sima , McLaughlin Peter , Plunkett William , Keating Michael 
Published: March 2003

Purpose: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia. Patients and Methods: The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia. Results: The starting dose of clofarabine (15 mg/m2) was myelosuppressive, requiring several dose de-escalations to 2 mg/m2, the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m2, with several escalations to 55 mg/m2. The DLT was reversible hepatotoxicity at 55 mg/m2. The recommended dose for acute leukemia phase II studies was 40 mg/m2. Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m2, the median plasma clofarabine level was 1.5 μmol/L (range, 0.42 to 3.2 μmol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate. Conclusion: This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m2 for solid tumors, the DLT being myelosuppression; and 40 mg/m2 for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.
Invasion Factors uPA/PAI-1 and HER2 Status Provide Independent and Complementary Information on Patient Outcome in Node-Negative Breast Cancer
Authors: Zemzoum Iris , Kates Ronald E. , Ross Jeffrey S. , Dettmar Peer , Dutta Moshumi , Henrichs Cordula , Yurdseven Suna , Höfler Heinz , Kiechle Marion , Schmitt Manfred , Harbeck Nadia 
Published: March 2003

Purpose: The independent clinical relevance of invasion factors urokinase-type plasminogen activator (uPA)/PAI-1 and HER2 status was evaluated in lymph node-negative breast cancer patients (N = 118) without adjuvant systemic therapy after long-term follow-up of more than 10 years (median, 126 months). Patients and Methods: Levels of uPA and its inhibitor PAI-1 were prospectively measured by enzyme-linked immunosorbent assay in primary tumor tissue extracts. HER2 gene amplification (HER2_AMP) was evaluated by fluorescence in situ hybridization (FISH; Ventana Medical Systems HER-2/neu probe; Tucson, AZ), and HER2 protein overexpression (HER2_EXP) was evaluated by immunohistochemistry (IHC; Oncogene Science antibody Ab-3; Cambridge, MA) on parallel-cut formalin-fixed paraffin-embedded tissue sections. Results: uPA/PAI-1 was high (either one or both factors were high) in 44% of the tumors. HER2_AMP was detected by FISH in 33% of the patients, and HER2_EXP was found by IHC in 44% of the patients. In a multivariate analysis of established and tumor-biologic prognostic factors, uPA/PAI-1 was the only independent prognostic factor for disease-free survival ([DFS]; P < .001; relative risk [RR], 8.3; 95% confidence interval [CI], 3.4 to 20.4). Although HER2_AMP and HER2_EXP did not reach significance for DFS, they were significant for overall survival (OS), even in multivariate analysis (HER2_AMP: P = .004; RR, 3.7; 95% CI, 1.5 to 9.2; HER2_EXP: P = .009; RR, 3.4; 95% CI, 1.4 to 8.7). Conclusion: After long-term follow-up, uPA/PAI-1 levels in primary tumor tissue reliably and strongly indicate an aggressive course of disease in lymph node-negative breast cancer independent of HER2 status. The particular prognostic effect of HER2 status on OS may reflect its ability to predict resistance to systemic therapy.
Early Detection of Response to Radiation Therapy in Patients With Brain Malignancies Using Conventional and High b-Value Diffusion-Weighted Magnetic Resonance Imaging
Authors: Mardor Yael , Pfeffer Raphael , Spiegelmann Roberto , Roth Yiftach , Maier Stephan E. , Nissim Ouzi , Berger Raanan , Glicksman Ami , Baram Jacob , Orenstein Arie , Cohen Jack S. , Tichler Thomas 
Published: March 2003

Purpose: To study the feasibility of using diffusion-weighted magnetic resonance imaging (DWMRI), which is sensitive to the diffusion of water molecules in tissues, for detection of early tumor response to radiation therapy; and to evaluate the additional information obtained from high DWMRI, which is more sensitive to low-mobility water molecules (such as intracellular or bound water), in increasing the sensitivity to response. Patients and Methods: Standard MRI and DWMRI were acquired before and at regular intervals after initiating radiation therapy for 10 malignant brain lesions in eight patients. Results: One week posttherapy, three of six responding lesions showed an increase in the conventional DWMRI parameters. Another three responding lesions showed no change. Four nonresponding lesions showed a decrease or no change. The early change in the diffusion parameters was enhanced by using high DWMRI. When high DWMRI was used, all responding lesions showed increase in the diffusion parameter and all nonresponding lesions showed no change or decrease. Response was determined by standard MRI 7 weeks posttherapy. The changes in the diffusion parameters measured 1 week after initiating treatment were correlated with later tumor response or no response (P < .006). This correlation was increased to P < .0006 when high DWMRI was used. Conclusion: The significant correlation between changes in diffusion parameters 1 week after initiating treatment and later tumor response or no response suggests the feasibility of using DWMRI for early, noninvasive prediction of tumor response. The ability to predict response may enable early termination of treatment in nonresponding patients, prevent additional toxicity, and allow for early changes in treatment.