bluuebunny/crossref_metadata_2025 huggingface dataset:
Monte Carlo Study of Dilute Solutions of Heteroarm Star Copolymers in Solvents Differing in Thermodynamic Quality
Authors: Havránková Jitka , Limpouchová Zuzana , Procházka Karel
Published: December 2005

Lattice Monte Carlo simulations (an original modification of the Siepmann and Frenkel simulation variant) was used to study the conformational behavior of heteroarm star copolymers star-(polystyrene; polyisoprene), PS8PI8, in a common good solvent for both types of arms (tetrahydrofuran) and in selective θ-solvents for both types of arms (in cyclohexane, i.e., in θ-solvent for PS and in 1,4-dioxane, i.e. in θ-solvent for PI). Results of simulations were compared with experimental data published by Pispas et al. The coarse graining procedure was performed to match the experimental behavior of heteroarm stars in a good solvent. The computer simulations reproduce all decisive trends of the conformational behavior for both selective solvents. The quantitative agreement between experimental and simulated size characteristics is very good. Simulations yield very detailed information on the system at the molecular level and show that the incompatible arms significantly segregate in selective solvents.
Efficient Synthesis of β-Aminoacrylates and β-Enaminones Catalyzed by Zn(OAc)2·2H2O
Authors: Vohra Ramandeep Kaur , Renaud Jean-Luc , Bruneau Christian
Published: December 2005

The direct condensation of amines with β-ketoesters and β-diketones to produce functional enamine derivatives has been investigated with zinc Lewis acid catalysts. Zn(OAc)2·2H2O shows good catalytic activity and leads to a chemo- and stereoselective formation of (Z)-enamine derivatives from aliphatic primary amines and ring-substituted anilines under mild conditions.
Distal adenomatous polyps are rare in patients with inflammatory bowel disease
Authors: Dixon A , Wurm P , Hart A , Robinson R
Published: January 2006

Objective

There is an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). The aim of this study was to compare the prevalence of left sided adenomas in patients with IBD aged 55–64 years with a local age matched control population.

Method

A review of clinical notes. The prevalence of adenomas in patients with IBD attending for either sigmoidoscopy or colonoscopy was compared with local age matched controls that participated in the national screening trial for colorectal cancer with flexible sigmoidoscopy.

Results

Of 106 patients (61 male, 45 female, mean age of 59 years), 80 suffered from ulcerative colitis, 20 from Crohn's disease, and six from indeterminate colitis. All patients had undergone at least one flexible sigmoidoscopy and 75 had a colonoscopy. Distal adenomas were found in three patients with ulcerative colitis compared with 67 of 749 controls (2.8% v 8.9%, χ2 = 4.6, p = 0.03).

Conclusions

The results suggest that distal adenomatous polyps are rare in patients aged 55–64 years with IBD compared with a control population. This supports the hypothesis that lesions other than polyps are important for the development of colorectal cancer in patients with IBD.
Long term prognosis of heart failure after acute coronary syndromes without ST elevation
Authors: Shibata M C , Collinson J , Taneja A K , Bakhai A , Flather M D
Published: January 2006

Background

Information about long term outcomes of patients with acute coronary syndromes (ACS) who have clinically diagnosed heart failure is scarce.

Methods

In a UK registry, this study evaluated patients with non-ST elevation ACS, recording treatment, and clinical outcomes for six months. In a subgroup, a four year mortality follow up was performed to estimate the impact of the clinical diagnosis of heart failure on survival.

Results

Of 1046 patients, 139 (13%) had a history of clinically diagnosed heart failure. At discharge, ACE inhibitors were prescribed for 58% and 28%, of those with and without a history of heart failure respectively (p<0.001). Rates of angiography, percutaneous intervention, and coronary artery bypass graft were 17.3% and 29.2% (p = 0.003), 5.0% and 8.4% (p = 0.17), and 5.0% and 7.5% (p = 0.3) for these groups respectively. Death or new myocardial infarction at six months occurred in 22% and 10% (p<0.001) and at four years death occurred in 60% and 20% of these groups respectively (p<0.001). In a multivariate analysis prior heart failure carried an odds ratio of 2.0 (p = 0.001) for death or myocardial infarction at six months and 2.4 (p<0.001) for death over four years. New heart failure was associated with an increased risk of death at six months (20% compared with 5%, p<0.001).

Conclusion

A clinical history of heart failure carries a substantial risk of death in patients admitted with ACS without ST elevation. Nearly 60% of those with prior heart failure are dead after four years. After adjustment for confounding factors, prior heart failure more than doubles the risk compared with those with no history.
ON A CLASS OF AUTOMATA GROUPS GENERALIZING LAMPLIGHTER GROUPS
Authors: SILVA P. V. , STEINBERG B.
Published: January 2006

We study automata groups generated by reset automata. Every lamplighter group ℤ/nℤ wr ℤ can be generated by such an automaton, and in general these automata groups are similar in nature to lamplighters: they are amenable locally-finite-by-cyclic groups; under mild decidable conditions, the semigroups generated by such automata are free. Parabolic subgroups and fractal properties are considered.
GENERALIZED COMPOSITION OF BINARY AGGREGATION OPERATORS
Authors: DURANTE FABRIZIO
Published: January 2006

We study a construction method for binary aggregation operators that generalizes the classical composition. Several examples are given, specially, in the class of aggregation operators with neutral element 1, e.g. semicopulas and copulas.
RECURSIVE AND ITERATIVE OWA OPERATORS
Authors: TROIANO LUIGI , YAGER RONALD R.
Published: January 2006

An important issue when using the OWA aggregation operators is the determination of weights. One approach is to link the weights to a desired attitudinal character for the aggregation. The ME-OWA operators provide a pioneering example of this approach. Here we first present an alternative approach to generating OWA weights with a desired attitudinal character. We accomplish this by using a family of recursive OWA operators (R-OWA). We then generalize this with a class that allows of OWA aggregation by iteration (It-OWA). Both families are built with the constraint of keeping constant the attitudinal character at any recursion or any iteration step. This is particularly useful in aggregations that sequentially add arguments to the aggregation.
A NOTE ON FIXED POINT THEOREM FOR FUZZY MAPPINGS
Authors: CHAKRABARTY KANKANA , NANDA SUDARSAN
Published: January 2006

This paper explores Heilpern's notions of fuzzy mapping and the fixed point theorem for fuzzy mappings. The fixed point theorem for fuzzy mappings as introduced by Heilpern has been generalized and some characterizations are done in this context.
BAYESIAN IDENTIFICATION OF MULTIPLE CHANGE POINTS IN POISSON DATA
Authors: LOSCHI R. H. , CRUZ F. R. B.
Published: January 2006

The identification of multiple change points is a problem shared by many subject areas, including disease and criminality mapping, medical diagnosis, industrial control, and finance. An algorithm based on the Product Partition Model (PPM) is developed to solve the multiple change point identification problem in Poisson data sequences. In order to address the PPM, a simple and easy way to implement Gibbs sampling scheme is derived. A sensitivity analysis is performed, for different prior specifications. The algorithm is then applied to the analysis of a real data sequence. The results show that the method is quite effective and provides useful inferences.
SIMULATION OF GEOGRAPHICAL TRENDS IN THE CHOWDHURY ECOSYSTEM MODEL
Authors: ROHDE KLAUS , STAUFFER DIETRICH
Published: January 2006

The Chowdhury model for ecosystems is modified by assuming a birth rate increasing with temperature, and additional minor changes. Its computer simulation based on individual births and deaths gives a biodiversity increasing from cold to warm climates. Complexity of foodwebs increases with time and at a higher rate at low latitudes, and there is a higher rate of species creation at low latitudes. Keeping many niches empty makes the results correspond more closely to natural gradients. All these findings are in good agreement with theoretical predictions and empirical findings, demonstrating that the Chowdhury model used for our simulations realistically reflects these.
Role of the arterial baroreflex in 5-HT1A receptor agonist-mediated sympathoexcitation following hypotensive hemorrhage
Authors: Osei-Owusu Patrick , Scrogin Karie
Published: January 2006

5-HT1A-receptor agonists rapidly restore blood pressure and sympathetic activity in conscious rats subjected to hypotensive hemorrhage. 5-HT1A-receptor activation has also been shown to produce a robust increase in baroreceptor-dependent, pulse-synchronous firing of cardiac sympathetic nerves in anesthetized cats. To determine whether 5-HT1A-receptor agonists reverse hemorrhage-induced suppression of sympathetic activity through facilitation of the arterial baroreflex, the effects of the 5-HT1A-receptor agonist, 8-OH-DPAT, were assessed in male Sprague-Dawley rats subjected to sinoaortic baroreceptor denervation and subsequent hypotensive hemorrhage. 8-OH-DPAT produced rapid pressor and sympathoexcitatory responses in hemorrhaged animals that were attenuated, but not blocked, by sinoaortic denervation (SAD) (+49 ± 4 vs. +37 ± 4 mmHg; +165 ± 30 vs. +92 ± 24% baseline, P < 0.01). Spectral analysis of sympathetic activity showed that SAD abolished the 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT)-mediated increases in pulse-synchronous (13 ± 1 vs. 5 ± 1% total power for intact vs. SAD rats, P < 0.01) and Mayer wave-related bursting (18 ± 3 vs. 8 ± 1% total power, P < 0.05). However, 8-OH-DPAT continued to increase total power (+72 ± 22 vs. −63 ± 7% prehemorrhage total power, P < 0.05) and power at the respiratory frequency (35 ± 2 vs. 25 ± 4% total power) in SAD animals. These data indicate that full expression of the sympathoexcitatory effect of 8-OH-DPAT requires a functional arterial baroreflex. However, a portion of the effect is due to activation of arterial baroreflex-independent sympathetic pathways.
Characterization of M-Current in Ventral Tegmental Area Dopamine Neurons
Authors: Koyama Susumu , Appel Sarah B.
Published: January 2006

M-current ( IM) is a voltage-gated potassium current (KCNQ type) that affects neuronal excitability and is modulated by some drugs of abuse. Ventral tegmental area (VTA) dopamine (DA) neurons are important for the reinforcing effects of drugs of abuse. Therefore we studied IMin acutely dissociated rat DA VTA neurons with nystatin-perforated patch recording. The standard deactivation protocol was used to measure IMduring voltage-clamp recording with hyperpolarizing voltage steps to −65 mV (in 10-mV increments) from a holding potential of −25 mV. IMamplitude was voltage dependent and maximal current amplitude was detected at −45 mV. The deactivation time constant of IMwas voltage dependent and became shorter at more negative voltages. The IM/KCNQ antagonist XE991 (0.3–30 μM) caused a concentration-dependent reduction in IMamplitude with an IC50of 0.71 μM. Tetraethylammonium (TEA, 0.3–10 mM) caused a concentration-dependent inhibition of IMwith an IC50of 1.56 mM. In current-clamp recordings, all DA VTA neurons were spontaneously active. Analysis of evoked action potential shape indicated that XE991 (1–10 μM) reduced the fast and slow components of the spike afterhyperpolarization (AHP) without affecting the middle component of the AHP. Action potential amplitude, duration, and threshold were not affected by XE991. In addition, 10 μM XE991 significantly shortened the interspike intervals in evoked spike trains. In conclusion, IMis active near threshold in DA VTA neurons, is blocked by XE991 (10 μM) and TEA (10 mM), may contribute to the shape of the AHP, and may decrease excitability of these neurons.
Ionic Currents Underlying Difference in Light Response Between Type A and Type B Photoreceptors
Authors: Blackwell K. T.
Published: January 2006

In Hermissenda crassicornis, the memory of light associated with turbulence is stored as changes in intrinsic and synaptic currents in both type A and type B photoreceptors. These photoreceptor types exhibit qualitatively different responses to light and current injection, and these differences shape the spatiotemporal firing patterns that control behavior. Thus the objective of the study was to identify the mechanisms underlying these differences. The approach was to develop a type B model that reproduced characteristics of type B photoreceptors recorded in vitro, and then to create a type A model by modifying a select number of ionic currents. Comparison of type A models with characteristics of type A photoreceptors recorded in vitro revealed that type A and type B photoreceptors have five main differences, three that have been characterized experimentally and two that constitute hypotheses to be tested with experiments in the future. The three differences between type A and type B photoreceptors previously characterized include the inward rectifier current, the fast sodium current, and conductance of calcium-dependent and transient potassium channels. Two additional changes were required to produce a type A photoreceptor model. The very fast firing frequency observed during the first second after light onset required a faster time constant of activation of the delayed rectifier. The fast spike adaptation required a fast, noninactivating calcium-dependent potassium current. Because these differences between type A and type B photoreceptors have not been confirmed in comparative experiments, they constitute hypotheses to be tested with future experiments.
Effects on Neural Function of Repleting Vitamin E–Deficient Rats With α-Tocopherol
Authors: Hayton Samantha M. , Kriss Tony , Wade Angie , Muller David P. R.
Published: January 2006

A severe and chronic deficiency of vitamin E (α-tocopherol) is associated with a characteristic neurological syndrome with typical “clinical,” neuropathological, and electrophysiological abnormalities in both humans and experimental animals. Repletion of vitamin E–deficient human subjects with α-tocopherol typically halts the progression of the neural signs and symptoms, and in some cases, can result in objective improvement. Electrophysiological parameters provide an objective measure of neural and visual function and improvement of some of these measures has been reported after repletion with vitamin E in humans. In this longitudinal study, the effects of repleting rats with a diet containing 36 mg/kg all-rac-α-tocopheryl acetate for 20 wk after they had been receiving a vitamin E–deficient diet for 38 wk was studied. We report significant improvements in growth and a number of electrophysiological parameters of both neural and visual function after repletion. These results confirm the validity of the vitamin E–deficient rat as a model of vitamin E deficiency in humans.
Spatially Specific fMRI Repetition Effects in Human Visual Cortex
Authors: Murray Scott O. , Olman Cheryl A. , Kersten Daniel
Published: January 2006

The functional MRI (fMRI) response to a pair of identical, successively presented stimuli can result in a smaller signal than the presentation of two nonidentical stimuli. This “repetition effect” has become a frequently used tool to make inferences about neural selectivity in specific cortical areas. However, little is known about the mechanism(s) underlying the effect. In particular, despite many successful applications of the technique in higher visual areas, repetition effects in lower visual areas [e.g., primary visual cortex (V1)] have been more difficult to characterize. One property that is well understood in early visual areas is the mapping of visual field locations to specific areas of the cortex (i.e., retinotopy). We used the retinotopic organization of V1 to activate progressively different populations of neurons in a rapid fMRI experimental design. We observed a repetition effect (reduced signal) when localized stimulus elements were repeated in identical locations. We show that this effect is spatially tuned and largely independent of both interstimulus interval (100–800 ms) and the focus of attention. Using the same timing parameters for which we observed a large effect of spatial position, we also examined the response to orientation changes and observed no effect of an orientation change on the response to repeated stimuli in V1 but significant effects in other retinotopic areas. Given these results, we discuss the possible causes of these repetition effects as well as the implications for interpreting other experiments that use this potentially powerful imaging technique.
Bortezomib Mediates Antiangiogenesis in Multiple Myeloma via Direct and Indirect Effects on Endothelial Cells
Authors: Roccaro Aldo Maria , Hideshima Teru , Raje Noopur , Kumar Shaji , Ishitsuka Kenji , Yasui Hiroshi , Shiraishi Norihiko , Ribatti Domenico , Nico Beatrice , Vacca Angelo , Dammacco Franco , Richardson Paul Gerard , Anderson Kenneth Carl
Published: January 2006

Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined.

In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient–derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF, IL-6, insulin-like growth factor-I, Angiopoietin 1 (Ang1), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu. (Cancer Res 2006; 66(1): 184-91)
An Imprinted Locus Epistatically Influences Nstr1 and Nstr2 to Control Resistance to Nerve Sheath Tumors in a Neurofibromatosis Type 1 Mouse Model
Authors: Reilly Karlyne M. , Broman Karl W. , Bronson Roderick T. , Tsang Shirley , Loisel Dagan A. , Christy Emily S. , Sun Zhonghe , Diehl John , Munroe David J. , Tuskan Robert G.
Published: January 2006

Cancer is a complex disease in which cells acquire many genetic and epigenetic alterations. We have examined how three types of alterations, mutations in tumor suppressor genes, changes in an imprinted locus, and polymorphic loci, interact to affect tumor susceptibility in a mouse model of neurofibromatosis type 1 (NF1). Mutations in tumor suppressor genes such as TP53 and in oncogenes such as KRAS have major effects on tumorigenesis due to the central roles of these genes in cell proliferation and cell survival. Imprinted genes expressed from only one parental chromosome affect tumorigenesis if their monoallelic expression is lost or duplicated. Because imprinted loci are within regions deleted or amplified in cancer, the parental origin of genomic rearrangements could affect tumorigenesis. Gene polymorphisms can vary tumor incidence by affecting rate-limiting steps in tumorigenesis within tumor cells or surrounding stroma. In our mouse model of NF1, the incidence of tumors mutant for the tumor suppressor genes Nf1 and Trp53 is strongly modified by a linked imprinted locus acting epistatically on two unlinked polymorphic loci, Nstr1 and Nstr2. This interaction of an imprinted locus and polymorphic susceptibility loci has profound implications for human mapping studies where the parental contribution of alleles is often unknown. (Cancer Res 2006; 66(1): 62-8)
Reversal of P-glycoprotein–Mediated Multidrug Resistance in Cancer Cells by the c-Jun NH2-Terminal Kinase
Authors: Zhou Jun , Liu Min , Aneja Ritu , Chandra Ramesh , Lage Hermann , Joshi Harish C.
Published: January 2006

A significant impediment to the success of cancer chemotherapy is multidrug resistance (MDR). A typical form of MDR is attributable to the overexpression of membrane transport proteins, such as P-glycoprotein, resulting in an increased drug efflux. In this study, we show that adenovirus-mediated enhancement of the c-Jun NH2-terminal kinase (JNK) reduces the level of P-glycoprotein in a dose- and time-dependent manner. Protein turnover assay shows that the decrease of P-glycoprotein is independent of its protein stability. Instead, this occurs primarily at the mRNA level, as revealed by reverse transcription-PCR analysis. We find that P-glycoprotein down-regulation requires the catalytic activity of JNK and is mediated by the c-Jun transcription factor, as either pharmacologic inhibition of JNK activity or dominant-negative suppression of c-Jun remarkably abolishes the ability of JNK to down-regulate P-glycoprotein. In addition, electrophoretic mobility shift assay reveals that adenoviral JNK increases the activator protein binding activity of the mdr1 gene in the MDR cells. We further show that the decrease of P-glycoprotein level is associated with a significant increase in intracellular drug accumulation and dramatically enhances the sensitivity of MDR cancer cells to chemotherapeutic agents. Our study provides the first direct evidence that enhancement of the JNK pathway down-regulates P-glycoprotein and reverses P-glycoprotein–mediated MDR in cancer cells. (Cancer Res 2006; 66(1): 445-52)
Paclitaxel-Induced Nuclear Translocation of FOXO3a in Breast Cancer Cells Is Mediated by c-Jun NH2-Terminal Kinase and Akt
Authors: Sunters Andrew , Madureira Patricia A. , Pomeranz Karen M. , Aubert Muriel , Brosens Jan J. , Cook Simon J. , Burgering Boudewijn M.T. , Coombes R. Charles , Lam Eric W.-F.
Published: January 2006

The microtubule-targeting compound paclitaxel is often used in the treatment of endocrine-resistant or metastatic breast cancer. We have previously shown that apoptosis of breast cancer cells in response to paclitaxel is mediated by induction of FOXO3a expression, a transcription factor downstream of the phosphatidylinositol-3-kinase/Akt signaling pathway. To further investigate its mechanism of action, we treated MCF-7 cells with paclitaxel and showed a dose-dependent increase in nuclear localization of FOXO3a, which coincided with decreased Akt signaling but increased c-Jun NH2-terminal kinase 1/2 (JNK1/2), p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) activity. Flow cytometry revealed that paclitaxel-induced apoptosis of MCF-7 cells and of other paclitaxel-sensitive breast cancer cell lines was maintained in the presence of inhibitors of p38 (SB203580) or mitogen-activated protein/ERK kinase 1 signaling (PD98059) but abrogated when cells were treated with the JNK1/2 inhibitor SP600125. SP600125 reversed Akt inhibition and abolished FOXO3a nuclear accumulation in response to paclitaxel. Moreover, conditional activation of JNK mimicked paclitaxel activity and led to dephosphorylation of Akt and FOXO3a. Furthermore, mouse embryonic fibroblasts (MEF) derived from JNK1/2 knockout mice displayed very high levels of active Akt, and in contrast to wild-type MEFs, paclitaxel treatment did not alter Akt activity or elicit FOXO3a nuclear translocation. Taken together, the data show that cell death of breast cancer cells in response to paclitaxel is dependent upon JNK activation, resulting in Akt inhibition and increased FOXO3a activity. (Cancer Res 2006; 66(1): 212-20)
Topological and Functional Discovery in a Gene Coexpression Meta-Network of Gastric Cancer
Authors: Aggarwal Amit , Li Guo Dong , Hoshida Yujin , Tsan Yuen Siu , Chu Kent-Man , So Samuel , Boussioutas Alex , Chen Xin , Bowtell David , Aburatani Hiroyuki , Leung Suet Yi , Tan Patrick
Published: January 2006

Gastric cancer is a leading cause of global cancer mortality, but comparatively little is known about the cellular pathways regulating different aspects of the gastric cancer phenotype. To achieve a better understanding of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we assembled and systematically analyzed a consensus gene coexpression meta-network of gastric cancer incorporating >300 tissue samples from four independent patient populations (the “gastrome”). We find that the gastrome exhibits a hierarchical scale-free architecture, with an internal structure comprising multiple deeply embedded modules associated with diverse cellular functions. Individual modules display distinct subtopologies, with some (cellular proliferation) being integrated within the primary network, and others (ribosomal biosynthesis) being relatively isolated. One module associated with intestinal differentiation exhibited a remarkably high degree of autonomy, raising the possibility that its specific topological features may contribute towards the frequent occurrence of intestinal metaplasia in gastric cancer. At the single-gene level, we discovered a novel conserved interaction between the PLA2G2A prognostic marker and the EphB2 receptor, and used tissue microarrays to validate the PLA2G2A/EphB2 association. Finally, because EphB2 is a known target of the Wnt signaling pathway, we tested and provide evidence that the Wnt pathway may also similarly regulate PLA2G2A. Many of these findings were not discernible by studying the single patient populations in isolation. Thus, besides enhancing our knowledge of gastric cancer, our results show the broad utility of applying meta-analytic approaches to genome-wide data for the purposes of biological discovery. (Cancer Res 2006; 66(1): 232-41)
Consistent Rearrangement of Chromosomal Band 6p21 with Generation of Fusion GenesJAZF1/PHF1andEPC1/PHF1in Endometrial Stromal Sarcoma
Authors: Micci Francesca , Panagopoulos Ioannis , Bjerkehagen Bodil , Heim Sverre
Published: January 2006

Endometrial stromal sarcomas (ESS) represent <10% of all uterine sarcomas. Cytogenetic data on this tumor type are limited to 32 cases, and the karyotypes are often complex, but the pattern of rearrangement is nevertheless clearly nonrandom with particularly frequent involvement of chromosome arms 6p and 7p. Recently, a specific translocation t(7;17)(p15;q21) leading to the fusion of two zinc finger genes, juxtaposed with another zinc finger (JAZF1) and joined to JAZF1 (JJAZ1), was described in a subset of ESS. We present three ESS whose karyotypes were without the disease-specific t(7;17) but instead showed rearrangement of chromosomal band 6p21, twice as an unbalanced t(6p;7p) and once as a three-way 6;10;10 translocation. All three tumors showed specific rearrangement of the PHD finger protein 1 (PHF1) gene, located in chromosomal band 6p21. In the two tumors with t(6;7), PHF1 was recombined with the JAZF1 gene from 7p15, leading to the formation of a JAZF1/PHF1 fusion gene. The third tumor showed a t(6p;10q;10p) as the sole karyotypic abnormality, leading to the fusion of PHF1 with another partner, the enhancer of polycomb (EPC1) gene from 10p11; EPC1 has hitherto not been associated with neoplasia. The PHF1 gene encodes a protein with two zinc finger motifs whose involvement in tumorigenesis and/or tumor progression has not been reported before, but its rearrangement clearly defines a new pathogenetic subgroup of ESS. (Cancer Res 2006; 66(1): 107-12)
Telomere Repeat Binding Factor 2 Interacts with Base Excision Repair Proteins and Stimulates DNA Synthesis by DNA Polymerase β
Authors: Muftuoglu Meltem , Wong Heng Kuan , Imam Syed Z. , Wilson David M. , Bohr Vilhelm A. , Opresko Patricia L.
Published: January 2006

The ends of linear chromosomes are capped and protected by protein-DNA complexes termed telomeres. Consequences of telomere dysfunction include genomic instability that can contribute to neoplastic transformation and progression. Telomere binding proteins interact with numerous proteins involved in DNA repair, underscoring the importance of regulating DNA repair pathways at telomeres. Telomeric DNA is particularly susceptible to oxidative damage, and such damage is repaired primarily via the base excision repair (BER) pathway. Using a screen for potential interactions between telomere repeat binding factor 2 (TRF2) and proteins involved in BER of oxidized bases in vitro, we found that TRF2 physically bound DNA polymerase β (Pol β) and flap endonuclease 1 (FEN-1). The interactions with endogenous proteins in human cell extracts were confirmed by coimmunoprecipitation experiments. The primary binding sites for both Pol β and FEN-1 mapped to the TRF2 NH2-terminal and COOH-terminal domains. We further tested the ability of TRF2 to modulate BER protein partners individually on a variety of substrates in vitro. TRF2 stimulated Pol β primer extension DNA synthesis on telomeric and nontelomeric primer/template substrates, resulting in up to a 75% increase in the proportion of longer products. TRF2 also stimulated Pol β strand displacement DNA synthesis in reconstituted BER reactions and increased the percent of long-patch BER intermediates on both telomeric and nontelomeric substrates. Potential roles of TRF2 in cooperation with BER proteins for DNA repair pathways at telomeres, as well as other genomic regions, are discussed. (Cancer Res 2006; 66(1): 113-24)
Physical and Functional Interaction between hMSH5 and c-Abl
Authors: Yi Wei , Lee Tai-Hsien , Tompkins Joshua D. , Zhu Fengxue , Wu Xiling , Her Chengtao
Published: January 2006

Despite being a member of the mismatch repair family of proteins, the biological functions of hMSH5 in human cells are presently elusive. Here, we report a novel physical and functional interaction between hMSH5 and c-Abl; the latter is a critical non–receptor tyrosine kinase involved in many critical cellular functions including DNA damage response, in which the kinase activity is normally suppressed in the absence of biological challenges. Our data indicate that hMSH5 associates with c-Abl in vivo, which is mediated by a direct physical interaction between the NH2 terminus (residues 1-109) of hMSH5 and the c-Abl SH3 domain. This physical interaction facilitates the activation of c-Abl tyrosine kinase and the phosphorylation of hMSH5 in response to ionizing radiation. Our data also indicate that the hMSH5 P29S variant overactivates the c-Abl tyrosine kinase activity. Furthermore, it seems that the tyrosine phosphorylation of hMSH5 promotes the dissociation of hMSH4-hMSH5 heterocomplex. Together, the revealed physical and functional interaction of hMSH5 with c-Abl implies that the interplay between hMSH5 and c-Abl could manipulate cellular responses to ionizing radiation–induced DNA damages. (Cancer Res 2006; 66(1): 151-8)
Proinflammatory CD4+CD45RBhi Lymphocytes Promote Mammary and Intestinal Carcinogenesis in Apc
Min/+ Mice
Authors: Rao Varada P. , Poutahidis Theofilos , Ge Zhongming , Nambiar Prashant R. , Horwitz Bruce H. , Fox James G. , Erdman Susan E.
Published: January 2006

Cancers of breast and bowel are increasingly frequent in humans. Chronic inflammation is known to be a risk factor for these malignancies, yet cellular and molecular mechanisms linking inflammation and carcinogenesis remain poorly understood. Here, we apply a widely used T-cell transfer paradigm, involving adoptive transfer of proinflammatory CD4+CD45RBhi (TE) cells to induce inflammatory bowel disease (IBD) in mice, to investigate roles of inflammation on carcinogenesis in the ApcMin/+ mouse model of intestinal polyposis. We find that transfer of TE cells significantly increases adenoma multiplicity and features of malignancy in recipient ApcMin/+ mice. Surprisingly, we find that female ApcMin/+ recipients of TE cells also rapidly develop mammary tumors. Both intestinal polyposis and mammary adenocarcinoma are abolished by cotransfer of anti-inflammatory CD4+CD45RBlo regulatory lymphocytes or by neutralization of key proinflammatory cytokine tumor necrosis factor-α. Lastly, down-regulation of cyclooxygenase-2 and c-Myc expression is observed coincident with tumor regression. These findings define a novel mouse model of inflammation-driven mammary carcinoma and suggest that epithelial carcinogenesis can be mitigated by anti-inflammatory cells and cytokines known to regulate IBD in humans and mice. (Cancer Res 2006; 66(1): 57-61)
Dose-Dependent Inhibition of the Post-Prandial Glycaemic Response to a Standard Carbohydrate Meal following Incorporation of Alpha-Cyclodextrin
Authors: Buckley Jonathan D. , Thorp Alicia A. , Murphy Karen J. , Howe Peter R.C.
Published: December 2005

Background: This study evaluated the dose-response effects of α-cyclodextrin, a cyclic oligosaccharide, on the glycaemic and insulinaemic responses to the consumption of a standard carbohydrate meal. Methods: In a double-blind, randomised, cross-over design, 10 healthy subjects consumed boiled white rice containing 50 g of digestible carbohydrate to which 0 (control), 2, 5 or 10 g of α-cyclodextrin was added. Plasma glucose and insulin concentrations were determined prior to and for 2 h after consumption of each meal. Results: The area under the plasma glucose curve was negatively related to the dose of α-cyclodextrin (r2 = 0.97, p = 0.02), with the areas being significantly reduced at the 5- and 10-gram doses compared with the control (p < 0.05). α-Cyclodextrin did not affect the area under the plasma insulin curve (p = 0.39). Higher doses of α-cyclodextrin resulted in greater satiety, but were associated with reduced palatability and an increased incidence of minor gastrointestinal complaints (stomach ache, nausea, bloating). Conclusion: α-Cyclodextrin reduces the glycaemic response to a standard carbohydrate meal in a dose-dependent manner and may be useful as an ingredient for reducing the glycaemic impact of such foods.
Relationship between Insulin Resistance and Lipid Peroxidation and Antioxidant Vitamins in Hypercholesterolemic Patients
Authors: Shin Min-Jeong , Park Eunju , Lee Jong Ho , Chung Namsik
Published: December 2005

Background: Several studies have reported that insulin resistance and compensatory hyperinsulinemia increased lipid peroxidation, suggesting the linking to each other. We investigated the relationships between insulin resistance index HOMA-IR and lipid peroxidation, plasma antioxidant status in non-diabetic, hypercholesterolemic patients. Methods: We measured the urinary excretion of 8-epi-prostaglandin F2α(PGF2α) levels as a measure of lipid peroxidation in vivo, total radical trapping antioxidant potential (TRAP) and fat-soluble antioxidant vitamins in 76 non-diabetic subjects with hypercholesterolemia (mean age 59 years, 25 males and 51 females). Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) derived from fasting glucose and insulin concentrations. Results: HOMA-IR was positively correlated with the urinary excretion of PGF2α (r = 0.222, p < 0.05) and negatively correlated with the TRAP (r = –0.211, p < 0.05) in total subjects. Furthermore, there were significant inverse relationships between HOMA-IR and lipid corrected fat-soluble vitamins such as β-carotene (r = –0.297, p < 0.01) and γ-tocopherol (r = –0.243, p < 0.05) and also significant inverse relation was found between lipid corrected β-carotene and the urinary PGF2αexcretion (r = –0.205, p < 0.05). When total subjects were divided into three groups according to tertiles of HOMA-IR, significant differences in urinary PGF2αexcretion (p < 0.05) and lipid corrected β-carotene (p < 0.005) among the three groups were observed. The highest HOMA-IR group had the higher levels of urinary PGF2αexcretion and lower levels of plasma β-carotene compared with the lowest HOMA-IR group. Conclusion: Our data showed that the insulin resistance of hypercholesterolemic patients increased oxidative stress and negatively influenced plasma antioxidant system. These results provide evidence in understanding mechanism linking insulin resistance and oxidative stress accompanied by reduced antioxidant system.
Outcome of Autogenous Fistula Construction in Hemodialyzed Patients Over 75 Years of Age
Authors: Weyde W. , Letachowicz W. , Kusztal M. , Porazko T. , Krajewska M. , Klinger M.
Published: December 2005

Background: There are controversies regarding the feasibility of autogenous vascular access creation in elderly hemodialysis (HD) patients. The aim of this retrospective study was to evaluate the results of creating different types of autogenous arteriovenous fistulas (AVFs) in a consecutive series of HD patients over 75 years of age. Methods: The analysis was performed in 131 patients (65 females, 66 males, average age 79.1 ± 3.6 years) in whom the creation of an autogenous AVF was considered within a 6-year period (February 1998 to February 2004). Among them, 26.7%were diabetics, 66.3% had hypertension, 30.7% were smokers, and 35.6% were obese. Patient survival and primary and secondary AVF patency were assessed. Results: The survival rates for patients were 94, 88, 66, and 45% at 6 months and at 1, 3, and 5 years, respectively. Successful autogenous AVF formation was finally achieved in 107 patients (81.6%): in 99 patients in the forearm and in 8in the upper arm. A Kaplan-Meier analysis showed primary AVF patency rates of: 74 ± 4.3% (± SE) at 1 month; 70 ± 4.7% at 6 months; 59 ± 4.9% at 1 year; 59 ± 4.9% at 2 years; 59± 4.9% at 3 years; 59 ± 4.9% at 4 years, and 58 ± 4.9% at 5 years. The secondary patency rates were: 95 ± 2.0; 92 ± 2.2; 84 ± 3.3; 79 ± 4.0; 72 ± 4.3; 71 ± 4.4, and 69 ± 4.5% in the corresponding periods, respectively. All postoperative complications in 10 patients were treated surgically, if applicable, without endovascular techniques. Conclusions: By exploiting all suitable types of autogenous AVF it is possible to establish the best form of vascular access even in the majority of elderly patients.
Cognition and the Sex Chromosomes: Studies in Turner Syndrome
Authors: Ross Judith , Roeltgen David , Zinn Andrew
Published: January 2006

Turner syndrome (TS) is a human genetic disorder involving females who lack all or part of one X chromosome. The complex phenotype includes ovarian failure, a characteristic neurocognitive profile and typical physical features. TS features are associated not only with complete monosomy X but also with partial deletions of either the short (Xp) or long (Xq) arm (partial monosomy X). Impaired visual-spatial/perceptual abilities are characteristic of TS children and adults of varying races and socioeconomic status, but global developmental delay is uncommon. The cognitive phenotype generally includes normal verbal function with relatively impaired visual-spatial ability, attention, working memory, and spatially dependent executive function. The constellation of neurocognitive deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities and hormonal deficiencies. Furthermore, other determinants, including an additional genetic mechanism, imprinting, may also contribute to cognitive deficits associated with monosomy X. As a relatively common genetic disorder with well-defined manifestations, TS presents an opportunity to investigate genetic and hormonal factors that influence female cognitive development. TS is an excellent model for such studies because of its prevalence, the well-characterized phenotype, and the wealth of molecular resources available for the X chromosome. In the current review, we summarize the hormonal and genetic factors that may contribute to the TS neurocognitive phenotype. The hormonal determinants of cognition in TS are related to estrogen and androgen deficiency. Our genetic hypothesis is that haploinsufficiency for gene/genes on the short arm of the X chromosome (Xp) is responsible for the hallmark features of the TS cognitive phenotype. Careful clinical and molecular characterization of adult subjects missing part of Xp links the TS phenotype of impaired visual spatial/perceptual ability to specific distal Xp chromosome regions. We demonstrate that small, nonmosaic deletion of the distal short arm of the X chromosome in adult women is associated with the same hallmark cognitive profile seen in adult women with TS. Future studies will elucidate the cognitive deficits and the underlying etiology. These results should allow us to begin to design cognitive interventions that might lessen those deficits in the TS population.
Complex Relationship Between Blood Pressure and Mortality in Type 2 Diabetic Patients
Authors: Rönnback Mats , Isomaa Bo , Fagerudd Johan , Forsblom Carol , Groop Per-Henrik , Tuomi Tiinamaija , Groop Leif
Published: December 2005

The presence of hypertension aggravates the high cardiovascular risk in type 2 diabetic patients. Pulse pressure is a marker of arterial stiffness and constitutes a risk factor for cardiovascular mortality. This study examines the relationship between different blood pressure indices and mortality in a cohort of type 2 diabetic patients. A total of 1294 type 2 diabetic patients with a median age of 69.1 years participated in the Botnia Study from 1990 to 1997. In 2004, after a median follow-up of 9.5 years, data on mortality was collected from the national population registry and hospital records. Systolic and diastolic blood pressure correlated negatively with mortality after adjustment for other risk factors. The association between low systolic and diastolic blood pressure and mortality was pronounced in patients with previous cardiovascular disease. A U-shaped association between pulse pressure and mortality was observed in elderly patients. These observations could be linked to arterial stiffness and heart failure. Low blood pressure in high-risk patients is likely to be a marker of poor health rather than the cause of mortality. The results suggest that the role of blood pressure as a risk marker in elderly type 2 diabetic patients with cardiovascular disease needs to be reevaluated.
A Category Theoretical Argument against the Possibility of Artificial Life: Robert Rosen's Central Proof Revisited
Authors: Chu Dominique , Ho Weng Kin
Published: December 2005

One of Robert Rosen's main contributions to the scientific community is summarized in his book Life itself. There Rosen presents a theoretical framework to define living systems; given this definition, he goes on to show that living systems are not realizable in computational universes. Despite being well known and often cited, Rosen's central proof has so far not been evaluated by the scientific community. In this article we review the essence of Rosen's ideas leading up to his rejection of the possibility of real artificial life in silico. We also evaluate his arguments and point out that some of Rosen's central notions are ill defined. The conclusion of this article is that Rosen's central proof is wrong.
Ant-Based Clustering and Topographic Mapping
Authors: Handl J. , Knowles J. , Dorigo M.
Published: December 2005

Ant-based clustering and sorting is a nature-inspired heuristic first introduced as a model for explaining two types of emergent behavior observed in real ant colonies. More recently, it has been applied in a data-mining context to perform both clustering and topographic mapping. Early work demonstrated some promising characteristics of the heuristic but did not extend to a rigorous investigation of its capabilities. We describe an improved version, called ATTA, incorporating adaptive, heterogeneous ants, a time-dependent transporting activity, and a method (for clustering applications) that transforms the spatial embedding produced by the algorithm into an explicit partitioning. ATTA is then subjected to the most rigorous experimental evaluation of an ant-based clustering and sorting algorithm undertaken to date: we compare its performance with standard techniques for clustering and topographic mapping using a set of analytical evaluation functions and a range of synthetic and real data collections. Our results demonstrate the ability of ant-based clustering and sorting to automatically identify the number of clusters inherent in a data collection, and to produce high quality solutions; indeed, we show that it is particularly robust for clusters of differing sizes and for overlapping clusters. The results obtained for topographic mapping are, however, disappointing. We provide evidence that the solutions generated by the ant algorithm are barely topology-preserving, and we explain in detail why results have—in spite of this—been misinterpreted (much more positively) in previous research.
Maintenance of Environmental Homeostasis by Biota, Selected Nonlocally by Circulation and Fluctuation Mechanisms
Authors: Akagi Tasuku
Published: December 2005

A simple abstract model is presented to show that a species with a favorable global effect on the whole biota (for example, by generating a moderate temperature range) can be selected through evolution. In the model, fluctuation in the growth rate among species leads to selection. The accompanying fluctuations in the quantity of resources, which return by circulation with a certain time lag, are likely to cause this selection. Different functions and various parameters are applied to the equations to monitor their effects on the whole system. In nature, producers satisfy the theoretical conditions of the model, implying the reality of the selection described by the mechanism presented here, during the history of the biota.
Neural Processing of Counting in Evolved Spiking and McCulloch-Pitts Agents
Authors: Saggie-Wexler Keren , Keinan Alon , Ruppin Eytan
Published: December 2005

This article investigates the evolution of autonomous agents that perform a memory-dependent counting task. Two types of neurocontrollers are evolved: networks of McCulloch-Pitts neurons, and spiking integrate-and-fire networks. The results demonstrate the superiority of the spiky model in evolutionary success and network simplicity. The combination of spiking dynamics with incremental evolution leads to the successful evolution of agents counting over very long periods. Analysis of the evolved networks unravels the counting mechanism and demonstrates how the spiking dynamics are utilized. Using new measures of spikiness we find that even in agents with spiking dynamics, these are usually truly utilized only when they are really needed, that is, in the evolved subnetwork responsible for counting.
Resilient Individuals Improve Evolutionary Search
Authors: Soule Terence
Published: December 2005

Results from the artificial life community show that under some conditions evolving populations converge on broader, but less fit peaks in the fitness landscape and avoid more fit, but narrower peaks. Results from the evolutionary computation community show that over time genotypes evolve to become more resilient, where resiliency (or genetic robustness) is defined as the ability of an individual to resist the potentially negative effects of genetic operations. This article demonstrates a previously unobserved evolutionary dynamic: in populations initially favoring a low, broad fitness peak, increases in resiliency result in the population shifting to a higher, narrower fitness peak. In these cases increasing resiliency is a necessary precondition for finding narrower peaks.