bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of Cytochromes P450 3A and P‐Glycoprotein in Human Large Intestinse in Paired Tumour and Normal Samples
Authors: Canaparo Roberto , Nordmark Anna , Finnström Niklas , Lundgren Stefan , Seidegård Janeric , Jeppsson Bengt , Edwards Robert J. , Boobis Alan R. , Rane Anders
Published: December 2006

Abstract: Our objective was to investigate the expression of different cytochromes P450 3A (CYP3A4,CYP3A5, andCYP3A7)andP‐glycoprotein (ABCB1) genes along the human large intestine in paired tumour and normal samples. Real‐time reverse transcriptase‐polymerase chain reaction was used to measureCYP3A4‐,CYP3A5‐,CYP3A7‐ andABCB1‐specific mRNA expression, and Western blot analysis was used to measure membrane protein levels of CYP3A4/7, CYP3A5 and P‐glycoprotein. Levels of mRNA and membrane protein fractions in the large intestine were compared with those of normal human liver. The mRNA expressions ofCYP3A4,CYP3A5,CYP3A7andABCB1in the large intestine were found to be highly variable, but overall the levels were significantly lower than those measured in liver (P < 0.0001,P < 0.001,P < 0.0001 andP < 0.01, respectively). At the membrane protein level, CYP3A4/7 was detected in all large intestine samples examined and the levels were substantially higher than those of the liver (P < 0.01). Although expression of CYP3A5 was detected in all large intestine samples, in most the levels were too low to allow quantification. P‐glycoprotein was readily detected at levels slightly higher than those of liver (P < 0.05). Comparison between paired samples of normal and tumour in large intestine showed no significant differences in either the mRNA or membrane protein levels of these genes. In conclusion, this work suggests a potential role of the large intestine in the absorption and metabolism of xenobiotics and nutrients and no difference in the CYP3A and P‐glycoprotein membrane protein fractions and mRNA expression between normal and tumour tissues.
Asparagine in plants
Authors: Lea P.J. , Sodek L. , Parry M.A.J. , Shewry P.R. , Halford N.G.
Published: December 2006

Interest in plant asparagine has rapidly taken off over the past 5 years following the report that acrylamide, a neurotoxin and potential carcinogen, is present in cooked foods, particularly carbohydrate‐rich foods such as wheat and potatoes which are subjected to roasting, baking or frying at high temperatures. Subsequent studies showed that acrylamide could be formed in foods by the thermal degradation of free asparagine in the presence of sugars in the Maillard reaction. In this article, our current knowledge of asparagine in plants and in particular its occurrence in cereal seeds and potatoes is reviewed and discussed in relation to acrylamide formation. There is now clear evidence that soluble asparagine accumulates in most if not all plant organs during periods of low rates of protein synthesis and a plentiful supply of reduced nitrogen. The accumulation of asparagine occurs during normal physiological processes such as seed germination and nitrogen transport. However, in addition, stress‐induced asparagine accumulation can be caused by mineral deficiencies, drought, salt, toxic metals and pathogen attack. The properties and gene regulation of the enzymes involved in asparagine synthesis and breakdown in plants are discussed in detail.
Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo
Authors: Conley Kevin E. , Amara Catherine E. , Jubrias Sharon A. , Marcinek David J.
Published: December 2006

Mitochondrial changes are at the centre of a wide range of maladies, including diabetes, neurodegeneration and ageing‐related dysfunctions. Here we describe innovative optical and magnetic resonance spectroscopic methods that non‐invasively measure key mitochondrial fluxes, ATP synthesis and O2 uptake, to permit the determination of mitochondrial coupling efficiency in vivo (P/O: half the ratio of ATP flux to O2 uptake). Three new insights result. First, mitochondrial coupling can be measured in vivo with the rigor of a biochemical determination and provides a gold standard to define well‐coupled mitochondria (P/O ≈ 2.5). Second, mitochondrial coupling differs substantially among muscles in healthy adults, from values reflective of well‐coupled oxidative phosphorylation in a hand muscle (P/O = 2.7) to mild uncoupling in a leg muscle (P/O = 2.0). Third, these coupling differences have an important impact on cell ageing. We found substantial uncoupling and loss of cellular [ATP] in a hand muscle indicative of mitochondrial dysfunction with age. In contrast, stable mitochondrial function was found in a leg muscle, which supports the notion that mild uncoupling is protective against mitochondrial damage with age. Thus, greater mitochondrial dysfunction is evident in muscles with higher type II muscle fibre content, which may be at the root of the preferential loss of type II fibres found in the elderly. Our results demonstrate that mitochondrial function and the tempo of ageing varies among human muscles in the same individual. These technical advances, in combination with the range of mitochondrial properties available in human muscles, provide an ideal system for studying mitochondrial function in normal tissue and the link between mitochondrial defects and cell pathology in disease.
Cholesterol‐dependent balance between evoked and spontaneous synaptic vesicle recycling
Authors: Wasser Catherine R. , Ertunc Mert , Liu Xinran , Kavalali Ege T.
Published: December 2006

Cholesterol is a prominent component of nerve terminals. To examine cholesterol's role in central neurotransmission, we treated hippocampal cultures with methyl‐β‐cyclodextrin, which reversibly binds cholesterol, or mevastatin, an inhibitor of cholesterol biosynthesis, to deplete cholesterol. We also used hippocampal cultures from Niemann‐Pick type C1‐deficient mice defective in intracellular cholesterol trafficking. These conditions revealed an augmentation in spontaneous neurotransmission detected electrically and an increase in spontaneous vesicle endocytosis judged by horseradish peroxidase uptake after cholesterol depletion by methyl‐β‐cyclodextrin. In contrast, responses evoked by action potentials and hypertonicity were severely impaired after the same treatments. The increase in spontaneous vesicle recycling and the decrease in evoked neurotransmission were reversible upon cholesterol addition. Cholesterol removal did not impact on the low level of evoked neurotransmission seen in the absence of synaptic vesicle SNARE protein synaptobrevin‐2 whereas the increase in spontaneous fusion remained. These results suggest that synaptic cholesterol balances evoked and spontaneous neurotransmission by hindering spontaneous synaptic vesicle turnover and sustaining evoked exo‐endocytosis.
Mathematical Model for a Universal Face Hobbing Hypoid Gear Generator
Authors: Shih Yi-Pei , Fong Zhang-Hua , Lin Grandle C. Y.
Published: December 2006

Based on the theory of gearing and differential geometry, a universal hypoid generator mathematical model for face hobbing spiral bevel and hypoid gears has been developed. This model can be used to simulate existing face hobbing processes, such as Oerlikon’s Spiroflex© and Spirac© methods, Klingelnberg’s Cyclo-Palloid© cutting system, and Gleason’s face hobbing nongenerated and generated cutting systems. The proposed model is divided into three modules: the cutter head, the imaginary generating gear, and the relative motion between the imaginary generating gear and the work gear. With such a modular arrangement, the model is suitable for development of object-oriented programming (OOP) code. In addition, it can be easily simplified to simulate face milling cutting and includes most existing flank modification features. A numerical example for simulation of the Klingelnberg Cyclo-Palloid© hypoid is presented to validate the proposed model, which can be used as a basis for developing a universal cutting simulation OOP engine for both face milling and face hobbing spiral bevel and hypoid gears.
Virtual-Power Flow and Mechanical Gear-Mesh Power Losses of Epicyclic Gear Trains
Authors: Chen Chao , Angeles Jorge
Published: December 2006

The concept of virtual power is first defined as the power measured, in a noninertial frame, in an epicyclic gear train. We then introduce the concept of virtual-power ratio, an invariant related to the power loss in an epicyclic system. It is shown that virtual-power flow and balance exist in an epicyclic gear train, based on which a novel algorithm to compute the gear-mesh powerloss and the train efficiency is formulated. This algorithm is general enough to be applied to any given epicyclic gear train. Our results are compared with previous work on the subject.
An Elite Source of Advice
Authors: Zimmerman Peter
Published: December 2006

The Jasons
. The Secret History of Science's Postwar Elite.
By Ann Finkbeiner
. Viking, New York, 2006. 336 pp. $27.95, C$39. ISBN 0-670-03489-4.

Drawing on interviews with past and present members, the author tells stories about this small group of scientists who have provided the U.S. government with behind-the-scenes advice on technical problems, es-pecially ones having military applications.
Heterogeneous Three-Dimensional Electronics by Use of Printed Semiconductor Nanomaterials
Authors: Ahn Jong-Hyun , Kim Hoon-Sik , Lee Keon Jae , Jeon Seokwoo , Kang Seong Jun , Sun Yugang , Nuzzo Ralph G. , Rogers John A.
Published: December 2006

We developed a simple approach to combine broad classes of dissimilar materials into heterogeneously integrated electronic systems with two- or three-dimensional layouts. The process begins with the synthesis of different semiconductor nanomaterials, such as single-walled carbon nanotubes and single-crystal micro- and nanoscale wires and ribbons of gallium nitride, silicon, and gallium arsenide on separate substrates. Repeated application of an additive, transfer printing process that uses soft stamps with these substrates as donors, followed by device and interconnect formation, yields high-performance heterogeneously integrated electronics that incorporate any combination of semiconductor nanomaterials on rigid or flexible device substrates. This versatile methodology can produce a wide range of unusual electronic systems that would be impossible to achieve with other techniques.
Greater Disruption Due to Failure of Inhibitory Control on an Ambiguous Distractor
Authors: Tsushima Yoshiaki , Sasaki Yuka , Watanabe Takeo
Published: December 2006

Considerable evidence indicates that a stimulus that is subthreshold, and thus consciously invisible, influences brain activity and behavioral performance. However, it is not clear how subthreshold stimuli are processed in the brain. We found that a task-irrelevant subthreshold coherent motion led to a stronger disturbance in task performance than did suprathreshold motion. With the subthreshold motion, activity in the visual cortex measured by functional magnetic resonance imaging was higher, but activity in the lateral prefrontal cortex was lower, than with suprathreshold motion. These results suggest that subthreshold irrelevant signals are not subject to effective inhibitory control.
Biomass, Size, and Trophic Status of Top Predators in the Pacific Ocean
Authors: Sibert John , Hampton John , Kleiber Pierre , Maunder Mark
Published: December 2006

Fisheries have removed at least 50 million tons of tuna and other top-level predators from the Pacific Ocean pelagic ecosystem since 1950, leading to concerns about a catastrophic reduction in population biomass and the collapse of oceanic food chains. We analyzed all available data from Pacific tuna fisheries for 1950–2004 to provide comprehensive estimates of fishery impacts on population biomass and size structure. Current biomass ranges among species from 36 to 91% of the biomass predicted in the absence of fishing, a level consistent with or higher than standard fisheries management targets. Fish larger than 175 centimeters fork length have decreased from 5% to approximately 1% of the total population. The trophic level of the catch has decreased slightly, but there is no detectable decrease in the trophic level of the population. These results indicate substantial, though not catastrophic, impacts of fisheries on these top-level predators and minor impacts on the ecosystem in the Pacific Ocean.
Infrared Spectroscopy of Comet 81P/Wild 2 Samples Returned by Stardust
Authors: Keller Lindsay P. , Bajt Sas̆a , Baratta Giuseppe A. , Borg Janet , Bradley John P. , Brownlee Don E. , Busemann Henner , Brucato John R. , Burchell Mark , Colangeli Luigi , d'Hendecourt Louis , Djouadi Zahia , Ferrini Gianluca , Flynn George , Franchi Ian A. , Fries Marc , Grady Monica M. , Graham Giles A. , Grossemy Faustine , Kearsley Anton , Matrajt Graciela , Nakamura-Messenger Keiko , Mennella Vito , Nittler Larry , Palumbo Maria E. , Stadermann Frank J. , Tsou Peter , Rotundi Alessandra , Sandford Scott A. , Snead Christopher , Steele Andrew , Wooden Diane , Zolensky Mike
Published: December 2006

Infrared spectra of material captured from comet 81P/Wild 2 by the Stardust spacecraft reveal indigenous aliphatic hydrocarbons similar to those in interplanetary dust particles thought to be derived from comets, but with longer chain lengths than those observed in the diffuse interstellar medium. Similarly, the Stardust samples contain abundant amorphous silicates in addition to crystalline silicates such as olivine and pyroxene. The presence of crystalline silicates in Wild 2 is consistent with mixing of solar system and interstellar matter. No hydrous silicates or carbonate minerals were detected, which suggests a lack of aqueous processing of Wild 2 dust.
Ultralow Thermal Conductivity in Disordered, Layered WSe
2
Crystals
Authors: Chiritescu Catalin , Cahill David G. , Nguyen Ngoc , Johnson David , Bodapati Arun , Keblinski Pawel , Zschack Paul
Published: December 2006

The cross-plane thermal conductivity of thin films of WSe
2
grown from alternating W and Se layers is as small as 0.05 watts per meter per degree kelvin at room temperature, 30 times smaller than the
c
-axis thermal conductivity of single-crystal WSe
2
and a factor of 6 smaller than the predicted minimum thermal conductivity for this material. We attribute the ultralow thermal conductivity of these disordered, layered crystals to the localization of lattice vibrations induced by the random stacking of two-dimensional crystalline WSe
2
sheets. Disordering of the layered structure by ion bombardment increases the thermal conductivity.
FREE ROTATION OF DOPANTS IN SUPERFLUID HELIUM CLUSTERS
Authors: PAOLINI S. , MORONI S.
Published: December 2006

We present quantum Monte Carlo calculations of the effective rotational constant B of several cromophore molecules embedded in He clusters, as a function of the cluster size. The predictive power of the computed B values is demonstrated not only by their agreement with available measurements, but also by their use in the assignment of several lines in both infrared and microwave spectra. The simulation results complement and extend the experimental information, offering insight into the relationship between structural and dynamical properties and the onset of superfluidity. The range of cluster sizes studied in our simulations includes systems of several tens particles, intermediate between the small-cluster and the nanodroplet regimes. In this size range we find unexpected trends for the evolution of B towards its asymptotic nano-droplet value.
PHASE TRANSITIONS IN ULTRA-COLD TWO-DIMENSIONAL BOSE GASES
Authors: HUTCHINSON D. A. W. , BLAKIE P. B.
Published: December 2006

We briefly review the theory of Bose-Einstein condensation in the two-dimensional trapped Bose gas and, in particular the relationship to the theory of the homogeneous two-dimensional gas and the Berezinskii-Kosterlitz-Thouless phase. We obtain a phase diagram for the trapped two-dimensional gas, finding a critical temperature above which the free energy of a state with a pair of vortices of opposite circulation is lower than that for a vortex-free Bose-Einstein condensed ground state. We identify three distinct phases which are, in order of increasing temperature, a phase coherent Bose-Einstein condensate, a vortex pair plasma with fluctuating condensate phase and a thermal Bose gas. The thermal activation of vortex-antivortex pair formation is confirmed using finite-temperature classical field simulations.
INTERMEDIATE SYMMETRIES IN ELECTRONIC SYSTEMS: DIMENSIONAL REDUCTION, ORDER OUT OF DISORDER, DUALITIES, AND FRACTIONALIZATION
Authors: NUSSINOV ZOHAR , BATISTA CRISTIAN D. , FRADKIN EDUARDO
Published: December 2006

We discuss symmetries intermediate between global and local and formalize the notion of dimensional reduction adduced from such symmetries. We apply this generalization to several systems including liquid crystalline phases of Quantum Hall systems, transition metal orbital systems, frustrated spin systems, ( p + ip ) superconducting arrays, and sliding Luttinger liquids. By considering space-time reflection symmetries, we illustrate that several of these systems are dual to each other. In some systems exhibiting these symmetries, low temperature local orders emerge by an "order out of disorder" effect while in other systems, the dimensional reduction precludes standard orders yet allows for multiparticle orders (including those of a topological nature).
COUPLED-CLUSTER THEORY FOR NUCLEI
Authors: PAPENBROCK T. , DEAN D. J. , GOUR J. R. , HAGEN G. , HJORTH-JENSEN M. , PIECUCH P. , WŁOCH M.
Published: December 2006

This presentation focuses on some of the recent developments in low-energy nuclear structure theory, with emphasis on applications of coupled-cluster theory. We report on results for ground and excited states in 4 He and 16 O , and about extensions of coupled-cluster theory to treat three-body forces.
ADVANCES IN KNOWLEDGE ACQUISITION AND REPRESENTATION
Authors: HOLDER LAWRENCE B. , MARKOV ZDRAVKO , RUSSELL INGRID
Published: December 2006

The articles in this special issue represent advances in several areas of knowledge acquisition and knowledge representation. In this article we attempt to place these advances in the context of a fundamental challenge in AI; namely, the automated acquisition of knowledge from data and the representation of this knowledge to support understanding and reasoning. We observe that while this work does indeed advance the field in important areas, the need exists to integrate these components into an end-to-end system and begin to extract general methodologies for this challenge. At the heart of this integration is the need for performance feedback throughout the process to guide the selection of alternative methods, the support for human interaction in the process, and the definition of general metrics and testbeds to evaluate progress.
MULTISCALE MORPHOLOGICAL WATERSHED SEGMENTATION FOR GRAY LEVEL IMAGE
Authors: LIU HAIHUA , CHEN ZHOUHUI , XIE CHANGSHENG
Published: December 2006

Multiscale image analysis has been used successfully in a number of applications to segment image features according to their relative scale. In this paper, we present a new framework for the hierarchical segmentation of gray level image. The proposed scheme comprises a nonlinear scale-space and morphological gradient watersheds. Our aim is to produce a meaningful hierarchy among the objects in the image. The scale-space is based on morphological anisotropic diffusion that uses reconstruction morphological operators. Furthermore, we introduce the method to reconstruct morphological operators and the principle of the dynamics of contours in scale-space that combines scale and contrast information. The performance of the proposed segmentation scheme is presented via experimental results obtained with a wide range of image including natural scenes.
MOLECULAR PATHOLOGY OF MALIGNANT GLIOMAS
Authors: Louis David N.
Published: December 2006

Malignant gliomas, the most common type of primary brain tumor, are a spectrum of tumors of varying differentiation and malignancy grades. These tumors may arise from neural stem cells and appear to contain tumor stem cells. Early genetic events differ between astrocytic and oligodendroglial tumors, but all tumors have an initially invasive phenotype, which complicates therapy. Progression-associated genetic alterations are common to different tumor types, targeting growth-promoting and cell cycle control pathways and resulting in focal hypoxia, necrosis, and angiogenesis. Knowledge of malignant glioma genetics has already impacted clinical management of these tumors, and researchers hope that further knowledge of the molecular pathology of malignant gliomas will result in novel therapies.
THE PATHOGENESIS OFHELICOBACTER PYLORI–INDUCED GASTRO-DUODENAL DISEASES
Authors: Atherton John C.
Published: December 2006

Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma. Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors. Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA. Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk. Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia. Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma. Falling prevalence of H. pylori in developed countries has led to a falling incidence of associated diseases. However, whether there are disadvantages of an H. pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear.
KSHV INFECTION AND THE PATHOGENESIS OF KAPOSI'S SARCOMA
Authors: Ganem Don
Published: December 2006

Kaposi's sarcoma (KS) has long been suspected of having an infectious etiology on the basis of its unusual epidemiology, histopathology, and natural history. Nearly a decade ago, a novel herpesviral genome was discovered in KS biopsies, and since that time strong epidemiologic evidence has accumulated correlating infection with this KS-associated herpesvirus (KSHV, also known as human herpesvirus 8) with the development of the disease. Here we review the evidence linking KSHV infection to KS risk and discuss current notions of how KSHV gene expression promotes the development of this remarkable neoplasm. These studies show that both latent and lytic viral replicative cycles contribute significantly—but differently—to KS development. The studies also highlight mechanistic differences between oncogenesis caused by KSHV and that caused by its distant relative Epstein-Barr virus.
A PATHOLOGIST'S ODYSSEY
Authors: Karnovsky Morris J.
Published: December 2006

I am honored to write the prefatory chapter for the inaugural volume of the Annual Review of Pathology: Mechanisms of Disease. This publishing venture signals that pathology takes its rightful place alongside the other biomedical sciences.

I thought it may be of interest to some to delineate how a circuitous path led me into a career in experimental pathology and to give some of the flavor of a past era in experimental approaches. Thus, my title.
CALCIUM IN CELL INJURY AND DEATH
Authors: Dong Zheng , Saikumar Pothana , Weinberg Joel M. , Venkatachalam Manjeri A.
Published: December 2006

Loss of Ca2+ homeostasis, often in the form of cytoplasmic increases, leads to cell injury. Depending upon cell type and the intensity of Ca2+ toxicity, the ensuing pathology can be reversible or irreversible. Although multiple destructive processes are activated by Ca2+, lethal outcomes are determined largely by Ca2+-induced mitochondrial permeability transition. This form of damage is primarily dependent upon mitochondrial Ca2+ accumulation, which is regulated by the mitochondrial membrane potential. Retention of the mitochondrial membrane potential during Ca2+ increases favors mitochondrial Ca2+ uptake and overload, resulting in mitochondrial permeability transition and cell death. In contrast, dissipation of mitochondrial membrane potential reduces mitochondrial Ca2+ uptake, retards mitochondrial permeability transition, and delays death, even in cells with large Ca2+ increases. The rates of mitochondrial membrane potential dissipation and mitochondrial Ca2+ uptake may determine cellular sensitivity to Ca2+ toxicity under pathological conditions, including ischemic injury.
Two weeks of high-intensity aerobic interval training increases the capacity for fat oxidation during exercise in women
Authors: Talanian Jason L. , Galloway Stuart D. R. , Heigenhauser George J. F. , Bonen Arend , Spriet Lawrence L.
Published: December 2006

Our aim was to examine the effects of seven high-intensity aerobic interval training (HIIT) sessions over 2 wk on skeletal muscle fuel content, mitochondrial enzyme activities, fatty acid transport proteins, peak O2consumption (V̇o2 peak), and whole body metabolic, hormonal, and cardiovascular responses to exercise. Eight women (22.1 ± 0.2 yr old, 65.0 ± 2.2 kg body wt, 2.36 ± 0.24 l/min V̇o2 peak) performed a V̇o2 peaktest and a 60-min cycling trial at ∼60% V̇o2 peakbefore and after training. Each session consisted of ten 4-min bouts at ∼90% V̇o2 peakwith 2 min of rest between intervals. Training increased V̇o2 peakby 13%. After HIIT, plasma epinephrine and heart rate were lower during the final 30 min of the 60-min cycling trial at ∼60% pretraining V̇o2 peak. Exercise whole body fat oxidation increased by 36% (from 15.0 ± 2.4 to 20.4 ± 2.5 g) after HIIT. Resting muscle glycogen and triacylglycerol contents were unaffected by HIIT, but net glycogen use was reduced during the posttraining 60-min cycling trial. HIIT significantly increased muscle mitochondrial β-hydroxyacyl-CoA dehydrogenase (15.44 ± 1.57 and 20.35 ± 1.40 mmol·min−1·kg wet mass−1before and after training, respectively) and citrate synthase (24.45 ± 1.89 and 29.31 ± 1.64 mmol·min−1·kg wet mass−1before and after training, respectively) maximal activities by 32% and 20%, while cytoplasmic hormone-sensitive lipase protein content was not significantly increased. Total muscle plasma membrane fatty acid-binding protein content increased significantly (25%), whereas fatty acid translocase/CD36 content was unaffected after HIIT. In summary, seven sessions of HIIT over 2 wk induced marked increases in whole body and skeletal muscle capacity for fatty acid oxidation during exercise in moderately active women.
Combination therapy with IFN-α plus bortezomib induces apoptosis and inhibits angiogenesis in human bladder cancer cells
Authors: Papageorgiou Angela , Kamat Ashish , Benedict William F. , Dinney Colin , McConkey David J.
Published: December 2006

In a recent study, we showed that the proteasome inhibitor bortezomib sensitizes human bladder cancer cells to IFN-induced cell death. Here, we characterized the molecular mechanisms underlying the antitumoral effects of the combination in more detail. Bortezomib synergized with IFN-α to promote apoptosis via a tumor necrosis factor–related apoptosis-inducing ligand–associated mechanism but did not inhibit production of proangiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8) in human UM-UC-5 cells. In contrast, exposure to the combination did not increase the levels of apoptosis in human UM-UC-3 cells but did inhibit the production of basic fibroblast growth factor and vascular endothelial growth factor. Studies with tumor xenografts confirmed that combination therapy with bortezomib plus IFN-α was effective in both models but that the effects were associated with differential effects on tumor necrosis factor–related apoptosis-inducing ligand–associated apoptosis (predominant in UM-UC-5) versus inhibition of angiogenesis (predominant in UM-UC-3). Together, our results show that combination therapy with IFN-α plus bortezomib is effective but can work via different mechanisms (apoptosis versus angiogenesis inhibition) in preclinical models of human bladder cancer. [Mol Cancer Ther 2006;5(12):3032–41]
RNA interference–mediated simultaneous down-regulation of urokinase-type plasminogen activator receptor and cathepsin B induces caspase-8–mediated apoptosis in SNB19 human glioma cells
Authors: Gondi Christopher S. , Kandhukuri Neelima , Kondraganti Shakuntala , Gujrati Meena , Olivero William C. , Dinh Dzung H. , Rao Jasti S.
Published: December 2006

The invasive character of gliomas depends on proteolytic cleavage of the surrounding extracellular matrix. Cathepsin B and urokinase-type plasminogen activator receptor (uPAR) together are known to be overexpressed in gliomas and, as such, are attractive targets for gene therapy. In the present study, we used plasmid constructs to induce the RNA interference (RNAi)–mediated down-regulation of uPAR and cathepsin B in SNB19 human glioma cells. We observed that the simultaneous down-regulation of uPAR and cathepsin B induces the up-regulation of proapoptotic genes and initiates a collapse in mitochondrial Δψ. Cathepsin B and uPAR down-regulated cells showed increases in the expression of activated caspase-8 and DFF40/caspase-activated DNase. Nuclear translocation of AIF and Fas ligand translocation to the cell membrane were also observed. Ki67 and X-linked inhibitor of apoptosis protein levels decreased, thereby indicating apoptosis. These results suggest the involvement of uPAR-cathepsin B complex on the cell surface and its role in maintaining the viability of SNB19 glioma cells. In conclusion, RNAi-mediated down-regulation of uPAR and cathepsin B initiates a partial extrinsic apoptotic cascade accompanied by the nuclear translocation of AIF. Our study shows the potential of RNAi-mediated down-regulation of uPAR and cathepsin B in developing new therapeutics for gliomas. [Mol Cancer Ther 2006;5(12):3197–208]
Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model
Authors: Bedogni Barbara , Welford Scott M. , Kwan Andrea C. , Ranger-Moore James , Saboda Kathylynn , Powell Marianne Broome
Published: December 2006

A number of human melanomas show hyperactivation of the Ras pathway due to mutations of the molecule or alteration of upstream or downstream effectors. In this study, we evaluated the effect of blocking the two Ras downstream pathways phosphatidylinositol-3-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal–regulated kinase on melanoma development and regression in the TPRas mouse model. The inhibition of these two signaling cascades by topically applied Ly294002 and U0126 significantly delayed melanoma development and significantly decreased the tumor incidence, particularly when the drugs were applied in combination. Treatment with the inhibitors of established melanomas resulted in complete remission in 33% of mice and partial regression in 46% of mice when drugs were delivered in combination. These responses correlated with increased apoptosis and decreased proliferation both in vitro and in vivo and reduced tumor angiogenesis. In conclusion, this study strongly supports the role of the phosphatidylinositol-3-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal–regulated kinase pathways in the development and maintenance of Ras-dependent melanomas and supports the notion that specific inhibition of these effectors may represent a very promising avenue for the treatment and prevention of the disease. [Mol Cancer Ther 2006;5(12):3071–7]
Influence of small interfering RNA corresponding to ets homologous factor on senescence-associated modulation of prostate carcinogenesis
Authors: Park Chaehwa , Lee Inkyoung , Kang Won Ki
Published: December 2006

Senescence is thought to be an inherent tumor-suppressive mechanism. In the process of identifying senescence-associated genes, we found significant suppression of the ets homologous factor (EHF) in cancer cells in a state of DNA damage–induced senescence. In this study, we show that EHF provides substantial drug resistance in PC-3 prostate cancer cells by inhibiting senescence and cell cycle arrest. Knockdown of EHF by small interfering RNA inhibited cell proliferation and induced a premature cellular senescence characterized by hypophosphorylation of Rb and increased level of p27, with concomitant decreases of cyclin A, cdc2, and E2F1. Telomeric repeat amplification protocol analysis showed that transient EHF knockdown significantly decreased telomerase activity, whereas this activity was increased by overexpression of EHF. In vivo tumorigenesis analyses revealed that tumors derived from EHF knockdown cells were significantly smaller than those derived from control cells (P < 0.0001). Further, the preestablished tumors were reduced after the injection of small interfering RNA corresponding to EHF (P = 0.0122). Collectively, these observations indicate that aberrant expression of EHF and the subsequent disruption of p27-mediated senescence and telomerase activity is likely to contribute significantly to tumor progression, and furthermore that EHF might be a promising target for future cancer therapeutics. [Mol Cancer Ther 2006;5(12):3191–6]
Stone Banging by Wild Capuchin Monkeys: An Unusual Auditory Display
Authors: de A. Moura Antonio Christian
Published: December 2006

Primates often react to possible predators by using intimidation displays, although the occurrence of these displays is dependent on the risk of predation. Functional explanations for these kinds of displays range from sexual selection to predator deterrence. The ability to respond to different predators can be socially acquired, and social traditions could explain population differences in response to the same potential predator. Here I report wild groups of Cebus apella libidinosus banging stones to produce sound in a remarkable aggressive display. I observed this display in 6 wild groups and I suggest its primary function is a predator-deterrent behaviour. Although banging objects is an innate behaviour in capuchin monkeys, in all wild groups observed so far it has been observed only in a foraging context. Stone banging is a novel behavioural variant that is most likely learned socially. The absence of this display in other populations of capuchins, which have access to stones, suggests that stone banging could be a social tradition in the population studied.
One-Male Harems and Female Social Dynamics in Guinea Baboons
Authors: Maestripieri Dario , Mayhew Jessica , Carlson Cindy L. , Hoffman Christy L. , Radtke Jennifer M.
Published: December 2006

Little is known about the mating system and social organization of Guinea baboons. This study investigated whether Guinea baboons have a harem-based mating system similar to that of hamadryas and gelada baboons and whether one-male mating units also correspond to social units. Ten adult females in a captive multi-male multi-female group of Guinea baboons were focally observed 2 h per week for 12 weeks, and all observed copulations within the group were recorded. Some males copulated with a single female while others had harems of 2–4 females. All females copulated with a single male except 1 female that switched harems early in the study. The focal females had higher rates of social interaction with their harem members, especially their harem male, than with individuals outside the harem. Females appeared to be subordinate to the harem male but little or no physical aggression or herding behavior from the male was observed. Variation in female social interactions within the harem was not accounted for by their sexual interactions with the male or their genetic relatedness with the females. Females, however, appeared to maintain social relationships with their female relatives in other harems. Taken together, the results of this study show that both mating and affiliative interactions in Guinea baboons are concentrated within one-male units and that the social dynamics within and between these units share some similarities as well as differences with those of hamadryas and gelada baboons.
Jordan: Communities and Community Genetics
Authors: Hamamy Hanan , Al-Hait Sana , Alwan Aladin , Ajlouni Kamel
Published: December 2006

The population in Jordan mounted from half a million in 1952 to 5.3 millions in 2004 and is composed of a variety of ethnic groups, the majority being Arabs. Couples nowadays tend to have fewer children, with the total fertility rate falling from 7.4 in 1976 to 3.7 in 2004. Consanguineous marriages are traditionally favored, with the preferred marriage partner being the offspring of the father’s brother. First-cousin marriages declined from 28.5% for marriages contracted between 1950 and 1979 to 19.5% for marriages contracted after 1980. In the overall population, carrier rates for β-thalassemia, α-thalassemia and sickle cell anemia are in the range of 2–4%, 3.2–12% of males have glucose-6-phosphate dehydrogenase deficiency, and the prevalences for familial Mediterranean fever and cystic fibrosis were estimated at around 0.04% each. A mandatory premarital screening program for β-thalassemia carriers commenced in June 2004. The high consanguinity rate and the large family size in Jordan have contributed to the description of a number of rare and new autosomal recessive conditions. Genetic services in Jordan are still scarce and do not cover all the country due to the major impediments of a paucity of resources and trained health professionals in the area of medical genetics. The demographic data suggest that the health system in Jordan is capable of introducing some basic community genetic services into the primary health care program through comprehensive and cost-effective programs.
Impact of the Change in CMS Billing Rules for Erythropoietin on Hemoglobin Outcomes in Dialysis Patients
Authors: Ofsthun Norma J. , Lazarus J. Michael
Published: December 2006

On April 1, 2006, new Centers for Medicare and Medicaid Services (CMS) rules for billing erythropoietin (EPO) for dialysis patients went into effect. Two key provisions of the rules were to cap the dose for a single patient at 500,000 IU/month and to mandate a 25% reduction in dose for patients whose latest hemoglobin (HGB) or hematocrit (HCT) in the prior month exceeded 13 g/dl or 39%, respectively. The purpose of this article is to document the effect of the rules change on HGB outcomes in a single large dialysis provider whose computer system was modified to enforce the rules. HGB and EPO doses for 5 months following the implementation were analyzed retrospectively. The most noteworthy observation is that while the rule appears to have reduced the percentage of patients with an HGB of >13 g/dl slightly, it has also increased the percentage of patients with HGB in the medically undesirable range of <11 g/dl.
The 2006 K/DOQI Guidelines for Peritoneal Dialysis Adequacy Are Not Adequate
Authors: Winchester James F. , Harbord Nikolas , Audia Patrick , Dubrow Alan , Gruber Stephen , Feinfeld Donald , Amerling Richard
Published: December 2006

The 2006 National Kidney Foundation K/DOQI guidelines have lowered the peritoneal dialysis adequacy standard of Kt/Vurea from 2.1 to 1.7 in anuric patients, largely based on the patient survival results of 2 clinical trials in Mexico and Hong Kong. It is our contention that the guidelines may be misleading since they have chosen to ignore the bias in these trials and have ignored the adverse outcomes in control groups in the trials on which the guidelines are based, as well as the body size of the subjects in these trials. Body size has changed in the US and Canada over the last few decades and there are similar changes worldwide. We suggest that the minimum targets for peritoneal dialysis be reinstituted at the previous standard Kt/Vurea of 2.0.
Usefulness of a Molecular Strategy for the Detection of Bacterial DNA in Patients with Severe Sepsis Undergoing Continuous Renal Replacement Therapy
Authors: Ratanarat Ranistha , Cazzavillan Stefania , Ricci Zaccaria , Rassu Mario , Segala Chiara , deCal Massimo , Cruz Dinna , Corradi Valentina , Manfro Stefania , Roessler Eric , Levin Nathan , Ronco Claudio
Published: December 2006

Introduction: Sepsis is a major cause of morbidity and mortality in critically ill patients. Sepsis is associated with cell necrosis and apoptosis. Circulating plasma levels of DNA have been found in conditions associated with cell death, including sepsis, pregnancy, stroke, myocardial infarction and trauma. Plasma DNA can also derive from bacteria. We have recently implemented a method to detect bacterial DNA and, in the present study, we validated this technique comparing it to standard blood culture in terms of diagnostic efficacy. Methods: We examined a cohort of 9 critically ill patients with a diagnosis of severe sepsis and acute renal failure requiring continuous renal replacement therapy (CRRT). We analyzed bacterial DNA in blood, hemofilters, and ultrafiltrate (UF) by polymerase chain reaction amplification of 16S rRNA gene sequence analysis. Standard blood cultures were performed for all patients. Results: The blood cultures from 2 of the 9 (22%) patients were positive. However, bacterial DNA was identified in the blood of 6 patients (67%), including the 2 septic patients with positive blood cultures. In 9 (100%) patients bacterial DNA was found on the filter blood side, whereas in 7 (78%) subjects it was found in the dialysate compartment of the hemofilters. Bacterial DNA was never detected in the UF. Conclusions: Using the 16S rRNA gene, the detection of bacterial DNA in blood and adsorbed within the filter could be a useful screening tool in clinically septic, blood culture-negative patients undergoing CRRT. However, the identification of the etiologic agent is not feasible with this technique because specific primers for the defined bacteria must be used to further identify the suspected pathogenic organisms.
The New KDOQITM Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and CKD
Authors: Nelson Robert G. , Tuttle Katherine R.
Published: December 2006

Background/Aims: The National Kidney Foundation (NKF) recently published new guidelines and clinical practice recommendations for the diagnosis and management of patients with diabetes and chronic kidney disease (CKD). Methods: Guidelines were developed using an evidence-based approach. When sufficient evidence was lacking, recommendations were developed that reflect expert opinion. Results: Guidelines describe the process for screening and diagnosis of kidney disease in the setting of diabetes and the management of hyperglycemia, hypertension, dyslipidemia, and nutrition. Recommendations describe the management of albuminuria in the normotensive diabetic patient and the potential value of albuminuria as a marker of treatment efficacy; the impact of diabetes and CKD in special populations; the importance of behavioral self-management; and the value of intensive multifaceted intervention in these high risk patients. Conclusions: The new guidelines and recommendations update and extend the scope of the NKF’s Kidney Disease Outcomes Quality Initiative (KDOQITM).
Coronary Artery Calcifications: A Critical Assessment of Imaging Techniques
Authors: Lembcke Alexander
Published: December 2006

The presence of coronary artery calcifications is a distinct marker of atherosclerosis and the severity of calcifications is claimed to reflect a patient’s individual plaque burden. Calcium deposits can be detected non-invasively by cardiac computed tomography (CT). This enables detection of coronary artery disease in a subclinical stage, description of the extent of the disease and risk estimation of future cardiovascular events. However, calcium quantification may also be used to monitor atherosclerotic disease, for example in the context of an intensified medical treatment. For years, electron-beam CT has been considered the gold-standard for calcium scoring. However, multi-slice spiral CT has recently captured the market and seems to achieve better measuring results with regard to the accuracy and reproducibility of calcium scores because of its superior image quality. For an optimal comparability of different CT techniques the calcium load should now be reported as absolute calcium mass rather than the traditional scoring methods.
Practical Approaches to Management of Hyperphosphatemia: Can We Improve the Current Situation?
Authors: Kuhlmann Martin K.
Published: December 2006

Despite advanced technology and regular and efficient dialysis treatment, the prevalence of hyperphosphatemia still is unacceptably high. Nevertheless, a neutral phosphorus balance level can generally be achieved by optimization of dialysis prescription in combination with individualized dietary and medical strategies. Besides increasing the fraction of inorganic phosphate (iP) removed by convection through the application of hemodiafiltration, extension of daily or weekly treatment time is the most promising way to neutralize phosphorus balance. Dietary phosphate restriction, the second corner stone of phosphate management, bears the risk of development of protein malnutrition. Phosphate binders (PBs) effectively reduce intestinal iP absorption, but are mostly dosed inadequately in relation to meal phosphorus content. Phosphate management may be substantially improved by enabling patients to self-adjust the PB dose to individual meal phosphate content, similar to self-adjusting insulin dose to carbohydrate intake by diabetics. A recently developed Phosphate Education Program (PEP) provides simple training tools to instruct patients to eye-estimate meal phosphorus content based on newly defined phosphorus units instead of milligrams. PEP is the first approach applying the concept of patient empowerment in the management of hyperphosphatemia in dialysis patients.
Selected Pharmacokinetic Issues in Patients with Chronic Kidney Disease
Authors: Churchwell Mariann D. , Mueller Bruce A.
Published: December 2006

Pharmacotherapy plays an important role in the care of a chronic kidney disease (CKD) patient but delivering this therapy can be challenging. Besides alterations in the pharmacokinetic parameters of absorption, distribution, metabolism and elimination, the average CKD patient must take multiple medications each day. The likelihood of an adverse drug reaction increases with each medication added to these patients’ daily regimen. In this article we discuss selected pharmacokinetic issues unique to CKD patients.
Promyelocytic Crisis of Chronic Myelogenous Leukaemia during Imatinib Mesylate Treatment
Authors: Oku Eijiro , Imamura Rie , Nagata Shuichiro , Takata Yuka , Seki Ritsuko , Otsubo Korenori , Hashiguchi Michitoshi , Osaki Koichi , Yakushiji Kazuaki , Yoshimoto Kohji , Ogata Hideaki , Sata Michio , Okamura Takashi
Published: December 2006

An untreated 66-year-old woman with chronic myelogenous leukaemia (CML) in the chronic phase was initially given imatinib mesylate, rapidly achieving a good cytogenetic response with treatment. However, acute promyelocytic leukaemia complicated by a disseminated intravascular coagulation occurred 9 months after beginning imatinib treatment. Promyelocytic crisis of CML was diagnosed by demonstration of both BCR/ABL and PML/RARα chimeric genes in leukaemic cells by karyotypic and fluorescence in situ hybridization analysis. Clonal evolution with addition of the PML/RARα translocation may have arisen in the early chronic phase of CML, with expansion of this clone during imatinib treatment. Promyelocytic crisis of CML is rare; furthermore, we know of no previous report of promyelocytic crisis occurring during treatment with imatinib.