bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathogens, density dependence and the coexistence of tropical trees
Authors: Freckleton Robert P , Lewis Owen T
Published: August 2006

There is increasing interest in the role played by density-dependent mortality from natural enemies, particularly plant pathogens, in promoting the coexistence and diversity of tropical trees. Here, we review four issues in the analysis of pathogen-induced density dependence that have been overlooked or inadequately addressed. First, the methodology for detecting density dependence must be robust to potential biases. Observational studies, in particular, require a careful analysis to avoid biases generated by measurement error, and existing studies could be criticized on these grounds. Experimental studies manipulating plant density and pathogen incidence will often be preferable, or should be run in parallel. Second, the form of density dependence is not well understood and, in particular, there are no data indicating whether pathogens cause compensating or overcompensating density responses. Owing to this, we argue that the potential for pathogen-induced density dependence to generate diversity-enhancing outcomes, such as the Janzen–Connell effect, remains uncertain, as coexistence is far more probable if density dependence is overcompensating. Third, there have been few studies examining the relative importance of intra- or interspecific density dependence resulting from pathogens (or, more widely, natural enemies). This is essentially equivalent to asking to what extent pathogens are host-specific. If pathogens are generalists, then mortality rates will respond to overall plant density, irrespective of plant species identity. This will weaken the intraspecific density dependence and reduce the diversity-promoting effects of pathogens. Finally, we highlight the need for studies that integrate observations and experiments on pathogens and density dependence into the whole life cycle of trees, because as yet it is not possible to be certain of the degree to which pathogens contribute to observed dynamics.
Introduction: new directions in liquid crystal science
Authors: Bruce Duncan W , Goodby John W , Sambles J. Roy , Coles Harry J
Published: August 2006

While we are all familiar with liquid crystal displays, an industry currently worth more than $60 billion yr
−1
and growing rapidly, fewer people are aware of the breadth of the subject of liquid crystals—one that represents the study of the fourth state of matter. Liquid crystals are found as essential elements in biological systems, soaps and detergents, sensor technologies and in the manipulation of electromagnetic radiation of various wavelengths. This meeting was designed to highlight both the truly multidisciplinary nature of liquid crystal science and to feature those areas away from electro-optic displays; these issues are developed and summarized in more detail.
Degradative transport of cationic amphiphilic drugs across phospholipid bilayers
Authors: Baciu Magdalena , Sebai Sarra C , Ces Oscar , Mulet Xavier , Clarke James A , Shearman Gemma C , Law Robert V , Templer Richard H , Plisson Christophe , Parker Christine A , Gee Antony
Published: August 2006

Drug molecules must cross multiple cell membrane barriers to reach their site of action. We present evidence that one of the largest classes of pharmaceutical drug molecules, the cationic amphiphilic drugs (CADs), does so via a catalytic reaction that degrades the phospholipid fabric of the membrane. We find that CADs partition rapidly to the polar–apolar region of the membrane. At physiological pH, the protonated groups on the CAD catalyse the acid hydrolysis of the ester linkage present in the phospholipid chains, producing a fatty acid and a single-chain lipid. The single-chain lipids rapidly destabilize the membrane, causing membranous fragments to separate and diffuse away from the host. These membrane fragments carry the drug molecules with them. The entire process, from drug adsorption to drug release within micelles, occurs on a time-scale of seconds, compatible with
in vivo
drug diffusion rates. Given the rate at which the reaction occurs, it is probable that this process is a significant mechanism for drug transport.
Pressure-jump X-ray studies of liquid crystal transitions in lipids
Authors: Seddon John M , Squires Adam M , Conn Charlotte E , Ces Oscar , Heron Andrew J , Mulet Xavier , Shearman Gemma C , Templer Richard H
Published: August 2006

In this paper, we give an overview of our studies by static and time-resolved X-ray diffraction of inverse cubic phases and phase transitions in lipids. In
§1
, we briefly discuss the lyotropic phase behaviour of lipids, focusing attention on non-lamellar structures, and their geometric/topological relationship to fusion processes in lipid membranes. Possible pathways for transitions between different cubic phases are also outlined. In
§2
, we discuss the effects of hydrostatic pressure on lipid membranes and lipid phase transitions, and describe how the parameters required to predict the pressure dependence of lipid phase transition temperatures can be conveniently measured. We review some earlier results of inverse bicontinuous cubic phases from our laboratory, showing effects such as pressure-induced formation and swelling. In
§3
, we describe the technique of pressure-jump synchrotron X-ray diffraction. We present results that have been obtained from the lipid system 1 : 2 dilauroylphosphatidylcholine/lauric acid for cubic–inverse hexagonal, cubic–cubic and lamellar–cubic transitions. The rate of transition was found to increase with the amplitude of the pressure-jump and with increasing temperature. Evidence for intermediate structures occurring transiently during the transitions was also obtained. In
§4
, we describe an IDL-based ‘
AXcess
’ software package being developed in our laboratory to permit batch processing and analysis of the large X-ray datasets produced by pressure-jump synchrotron experiments. In
§5
, we present some recent results on the fluid lamellar–
Pn
3
m
cubic phase transition of the single-chain lipid 1-monoelaidin, which we have studied both by pressure-jump and temperature-jump X-ray diffraction. Finally, in
§6
, we give a few indicators of future directions of this research. We anticipate that the most useful technical advance will be the development of pressure-jump apparatus on the microsecond time-scale, which will involve the use of a stack of piezoelectric pressure actuators. The pressure-jump technique is not restricted to lipid phase transitions, but can be used to study a wide range of soft matter transitions, ranging from protein unfolding and DNA unwinding and transitions, to phase transitions in thermotropic liquid crystals, surfactants and block copolymers.
Uniaxial and biaxial nematic liquid crystals
Authors: Dingemans T.J , Madsen L.A , Zafiropoulos N.A , Lin Wenbin , Samulski E.T
Published: August 2006

The unusual exhibition of a biaxial nematic phase in nonlinear thermotropic mesogens derived from the 2,5-oxadiazole biphenol (ODBP) core is placed in a general context; the uniaxial nematic phase of the prototypical rod-like mesogen
para
-quinquephenyl does not follow the classical mean-field behaviour of nematics, thus questioning the utility of such theories for quantitative predictions about biaxial nematics. The nuclear magnetic resonance spectra of labelled probe molecules dissolved in ODBP biaxial nematic phases suggest that a second critical rotation frequency, related to the differences in the transverse diamagnetic susceptibilities of the biaxial nematic, must be exceeded in order to create an aligned two-dimensional powder sample. Efforts to find higher viscosity and lower temperature biaxial nematics (with lower critical rotation rates) to confirm the above conjecture are described. Several chemical modifications of the ODBP mesogenic core are presented.
The effect of size and shape variation in discotic liquid crystals based on triphenylene cores
Authors: Cammidge Andrew N
Published: August 2006

The triphenylene core provides a versatile platform from which discotic liquid crystals can be constructed. Synthetic advances permit the effect that substantial or subtle variation on structure has on mesophase formation. Through comparison of many derivatives, from our studies and others, it appears that the discotic core should be viewed as the triphenylene unit plus the attached polarizable substituents. Disruption of these extended cores discourages mesophase formation.
Bioinspired supramolecular liquid crystals
Authors: Percec Virgil
Published: August 2006

A brief account on the historical events leading to the discovery of self-assembling dendrons that generate self-organizable supramolecular dendrimers, or supramolecular polymers, and self-organizable dendronized polymers is provided. These building blocks were accessed by an accelerated design strategy that involves structural and retrostructural analysis of periodic and quasi-periodic assemblies. This design strategy mediated the discovery of porous helical supramolecular structures that self-assembled from dendritic dipeptides. Helical porous columns are the closest mimics of biologically related structures, such as tobacco mosaic virus coat, porous transmembrane proteins, porous pathogens and antibiotics. It is expected that this concept will allow one to investigate the structural origin of functions in synthetic supramolecular materials.
Metal slits and liquid crystals at microwave frequencies
Authors: Sambles J. Roy , Kelly Robert , Yang Fuzi
Published: August 2006

While the use of liquid crystals (LCs) over the visible region is ubiquitous in flat-screen displays, there has been little by the way of applications at other wavelengths. Specifically, notwithstanding the continuing permittivity anisotropy to be found at longer wavelengths, there has been virtually no development in the microwave domain. This is largely due to the fact that scaling up the micrometer-thick LC layers used for visible radiation to millimetre dimensions is seen as impractical. In this study, it is shown how, using thin slits in metal structures, a completely new generation of LC devices for use at microwaves may be realized. Such structures include slatted metal Fabry–Perot resonators, beam-steering devices, thin flexible voltage tunable filters and even cascade structures with strongly enhanced and reshaped microwave fields.
Gelation versus liquid crystal phase transitions in suspensions of plate-like particles
Authors: Mourad M.C.D , Wijnhoven J.E.G.J , van 't Zand D.D , van der Beek D , Lekkerkerker H.N.W
Published: August 2006

Gelation is a common effect in aqueous suspensions of charged colloidal clay platelets at concentrations as low as 1 wt%. However, in systems of charged gibbsite [Al(OH)
3
] platelets, gelation can be delayed to concentrations as high as 50 wt% depending on the ionic strength. We investigated the phase behaviour of this system approaching the state of gelation in the delicate region between attractive and repulsive states that originate from competition between Coulomb repulsion and van der Waals attraction. As a function of the ionic strength, isotropic–nematic, nematic–columnar and isotropic–columnar phase separations were observed. Moreover, compression by gravitational forces allowed us to observe phase separation that is arrested by gelation in the homogeneous suspensions.
Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor
Authors: Miller Julie J. , Summers Matthew K. , Hansen David V. , Nachury Maxence V. , Lehman Norman L. , Loktev Alex , Jackson Peter K.
Published: August 2006

The periodic destruction of mitotic cyclins is triggered by the activation of the anaphase-promoting complex/cyclosome (APC/C) in mitosis. Although the ability of the APC/C to recognize destruction box (D-box) substrates oscillates throughout the cell cycle, the mechanism regulating APC/C binding to D-box substrates remains unclear. Here, we show that the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator, binds to the D-box receptor site on the APC/CCdh1, and competes with APC/C substrates for D-box binding. Emi1 itself contains a conserved C-terminal D-box, which provides APC/C-binding affinity, and a conserved zinc-binding region (ZBR), which antagonizes APC/C E3 ligase activity independent of tight APC binding. Mutation of the ZBR converts Emi1 into a D-box-dependent APC/C substrate. The identification of a direct Emi1–APC/C complex further explains how Emi1 functions as a stabilizing factor for cyclin accumulation and the need to destroy Emi1 for APC/C activation in mitosis. The combination of a degron/E3 recognition site and an anti-ligase function in Emi1 suggests a general model for how E3 substrates evolve to become pseudosubstrate inhibitors.
Suppression of LX Ribonuclease in Tomato Results in a Delay of Leaf Senescence and Abscission
Authors: Lers Amnon , Sonego Lilian , Green Pamela J. , Burd Shaul
Published: August 2006

Although present in different organisms and conserved in their protein sequence, the biological functions of T2 ribonucleases (RNase) are generally unknown. Tomato (Lycopersicon esculentum) LX is a T2/S-like RNase and its expression is known to be associated with phosphate starvation, ethylene responses, and senescence and programmed cell death. In this study, LX function was investigated using antisense tomato plants in which the LX protein level was reduced. LX protein levels normally become elevated when leaves senesce and antisense inhibition of LX retarded the progression of senescence. Moreover, we observed a marked delay of leaf abscission in LX-deficient plants. This correlated with specific induction of LX protein in the tomato mature abscission zone tissue. LX RNase gene regulation and the consequences of antisense inhibition indicate that LX has an important functional role in both abscission and senescence.
Gibberellin Mobilizes Distinct DELLA-Dependent Transcriptomes to Regulate Seed Germination and Floral Development in Arabidopsis
Authors: Cao Dongni , Cheng Hui , Wu Wei , Soo Hui Meng , Peng Jinrong
Published: August 2006

Severe Arabidopsis (Arabidopsis thaliana) gibberellin (GA)-deficient mutant ga1-3 fails to germinate and is impaired in floral organ development. In contrast, the ga1-3 gai-t6 rga-t2 rgl1-1 rgl2-1 mutant confers GA-independent seed germination and floral development. This fact suggests that GA-regulated transcriptomes for seed germination and floral development are DELLA dependent. However, it is currently not known if all GA-regulated genes are GA regulated in a DELLA-dependent fashion and if a similar set of DELLA-regulated genes is mobilized to repress both seed germination and floral development. Here, we compared the global gene expression patterns in the imbibed seeds and unopened flower buds of the ga1-3 mutant with that of the wild type and of the ga1-3 gai-t6 rga-t2 rgl1-1 rgl2-1 mutant. We found that about one-half of total GA-regulated genes are apparently regulated in a DELLA-dependent fashion, suggesting that there might be a DELLA-independent or -partially-dependent component of GA-dependent gene regulation. A cross-comparison based on gene identity revealed that the GA-regulated DELLA-dependent transcriptomes in the imbibed seeds and flower buds are distinct from each other. Detailed ontology analysis showed that, on one hand, DELLAs differentially regulate the expression of different individual members of a gene family to run similar biochemical pathways in seeds and flower. Meanwhile, DELLAs control many functionally different genes to run specific pathways in seeds or flower buds to mark the two different developmental processes. Our data shown here not only confirm many previous reports but also single out some novel aspects of DELLA functions that are instructive to our future research.
Species Having C4 Single-Cell-Type Photosynthesis in the Chenopodiaceae Family Evolved a Photosynthetic Phosphoenolpyruvate Carboxylase Like That of Kranz-Type C4 Species
Authors: Lara María Valeria , Chuong Simon D.X. , Akhani Hossein , Andreo Carlos Santiago , Edwards Gerald E.
Published: August 2006

Spatial and temporal regulation of phosphoenolpyruvate carboxylase (PEPC) is critical to the function of C4 photosynthesis. The photosynthetic isoform of PEPC in the cytosol of mesophyll cells in Kranz-type C4 photosynthesis has distinctive kinetic and regulatory properties. Some species in the Chenopodiaceae family perform C4 photosynthesis without Kranz anatomy by spatial separation of initial fixation of atmospheric CO2 via PEPC from C4 acid decarboxylation and CO2 donation to Rubisco within individual chlorenchyma cells. We studied molecular and functional features of PEPC in two single-cell functioning C4 species (Bienertia sinuspersici, Suaeda aralocaspica) as compared to Kranz type (Haloxylon persicum, Salsola richteri, Suaeda eltonica) and C3 (Suaeda linifolia) chenopods. It was found that PEPC from both types of C4 chenopods displays higher specific activity than that of the C3 species and shows kinetic and regulatory characteristics similar to those of C4 species in other families in that they are subject to light/dark regulation by phosphorylation and display differential malate sensitivity. Also, the deduced amino acid sequence from leaf cDNA indicates that the single-cell functioning C4 species possesses a Kranz-type C4 isoform with a Ser in the amino terminal. A phylogeny of PEPC shows that isoforms in the two single-cell functioning C4 species are in a clade with the C3 and Kranz C4  Suaeda spp. with high sequence homology. Overall, this study indicates that B. sinuspersici and S. aralocaspica have a C4-type PEPC similar to that in Kranz C4 plants, which likely is required for effective function of C4 photosynthesis.
A Cytosolic Arabidopsis d-Xylulose Kinase Catalyzes the Phosphorylation of 1-Deoxy-d-Xylulose into a Precursor of the Plastidial Isoprenoid Pathway
Authors: Hemmerlin Andréa , Tritsch Denis , Hartmann Michael , Pacaud Karine , Hoeffler Jean-François , van Dorsselaer Alain , Rohmer Michel , Bach Thomas J.
Published: August 2006

Plants are able to integrate exogenous 1-deoxy-d-xylulose (DX) into the 2C-methyl-d-erythritol 4-phosphate pathway, implicated in the biosynthesis of plastidial isoprenoids. Thus, the carbohydrate needs to be phosphorylated into 1-deoxy-d-xylulose 5-phosphate and translocated into plastids, or vice versa. An enzyme capable of phosphorylating DX was partially purified from a cell-free Arabidopsis (Arabidopsis thaliana) protein extract. It was identified by mass spectrometry as a cytosolic protein bearing d-xylulose kinase (XK) signatures, already suggesting that DX is phosphorylated within the cytosol prior to translocation into the plastids. The corresponding cDNA was isolated and enzymatic properties of a recombinant protein were determined. In Arabidopsis, xylulose kinases are encoded by a small gene family, in which only two genes are putatively annotated. The additional gene is coding for a protein targeted to plastids, as was proved by colocalization experiments using green fluorescent protein fusion constructs. Functional complementation assays in an Escherichia coli strain deleted in xk revealed that the cytosolic enzyme could exclusively phosphorylate xylulose in vivo, not the enzyme that is targeted to plastids. xk activities could not be detected in chloroplast protein extracts or in proteins isolated from its ancestral relative Synechocystis sp. PCC 6803. The gene encoding the plastidic protein annotated as “xylulose kinase” might in fact yield an enzyme having different phosphorylation specificities. The biochemical characterization and complementation experiments with DX of specific Arabidopsis knockout mutants seedlings treated with oxo-clomazone, an inhibitor of 1-deoxy-d-xylulose 5-phosphate synthase, further confirmed that the cytosolic protein is responsible for the phosphorylation of DX in planta.
The Balance between Cell Division and Endoreplication Depends on E2FC-DPB, Transcription Factors Regulated by the Ubiquitin-SCFSKP2A Pathway inArabidopsis
Authors: del Pozo Juan C. , Diaz-Trivino Sara , Cisneros Nerea , Gutierrez Crisanto
Published: August 2006

The balance between cell proliferation, cell cycle arrest, and differentiation needed to maintain the organogenetic program depends on the coordination of gene expression, posttranslational modification, and specific proteolysis of cell cycle regulators. The G1/S and G2/M transitions are critical checkpoints controlled, in part, by cyclin-dependent kinases in the retinoblastoma (RBR)/E2F/DP pathway. Arabidopsis thaliana DPB is regulated by phosphorylation and targeted to proteasome-mediated proteolysis by the SCFSKP2A complex. In addition, DPB interacts in vivo with E2FC, because ectopic coexpression of E2FC and DPB produces severe developmental defects. To understand E2FC/DPB heterodimer function, we analyzed the effect of reducing E2FC mRNA levels with RNA interference. The e2fc-R plants developed organs with more but smaller cells and showed increased cell cycle marker gene expression and increased proliferative activity in developing leaves, meristems, and pericycle cells. This last feature produces plants with more lateral roots, consistent with an E2FC role in restricting lateral root initiation. The e2fc-R plants also show marked reductions in ploidy levels of mature leaves. These results indicate that the transition from cell division to the endocycle is sensitive to different pathways, E2FC/DPB being one of them. Our results show that E2FC/DPB is a key factor in controlling the balance between cell proliferation and the switch to the endocycle program.
Higher‐level phylogeny of the Ithomiinae (Lepidoptera: Nymphalidae): classification, patterns of larval hostplant colonization and diversification
Authors: Willmott Keith R. , Freitas André V. L.
Published: August 2006

We present a higher‐level phylogenetic hypothesis for the diverse neotropical butterfly subfamily Ithomiinae, inferred from one of the largest non‐molecular Lepidoptera data sets to date, including 106 species (105 ingroup) and 353 characters (306 informative) from adult and immature stage morphology and ecology. Initial analyses resulted in 1716 most parsimonious trees, which were reduced to a single tree after successive approximations character weighting. The inferred phylogeny was broadly consistent with other past and current work. Although some deeper relationships are uncertain, tribal‐level clades were generally strongly supported, with two changes required to existing classification. The tribe Melinaeini is polyphyletic andAthesis + Patriciarequire a new tribe. Methonashould be removed from Mechanitini into the restored tribe Methonini. Dircennini was paraphyletic in analyses of all data but monophyletic based on adult morphology alone, and its status remains to be confirmed.Hypothyris,Episcada,Godyris,HypoleriaandGretaare paraphyletic. A simulation analysis showed that relatively basal branches tended to have higher partitioned Bremer support for immature stage characters. Larval hostplant records were optimized on to a reduced, generic‐level phylogeny and indicate that ithomiines moved from Apocynaceae to Solanaceae twice, or that Tithoreini re‐colonized Apocynaceae after a basal shift to Solanaceae. Ithomiine clades have specialized on particular plant clades suggesting repeated colonization of novel hostplant niches consistent with adaptive radiation. The shift toSolanum, comprising 70% of neotropical Solanaceae, occurs at the base of a clade containing 89% of all ithomiines, and is interpreted as the major event in the evolution of ithomiine larval hostplant relationships.

© The Willi Hennig Society 2006.
Rejecting “the given” in systematics
Authors: Kearney Maureen , Rieppel Olivier
Published: August 2006

How morphology and systematics come together through morphological analysis, homology hypotheses and phylogenetic analysis is a topic of continuing debate. Some contemporary approaches reject biological evaluation of morphological characters and fall back on an atheoretical and putatively objective (but, in fact, phenetic) approach that defers to the test of congruence for homology assessment. We note persistent trends toward an uncritical empiricism (where evidence is believed to be immediately “given” in putatively theory‐free observation) and instrumentalism (where hypotheses of primary homology become mere instruments with little or no empirical foundation for choosing among competing phylogenetic hypotheses). We suggest that this situation is partly a consequence of the fact that the test of congruence and the related concept of total evidence have been inappropriately tied to a Popperian philosophy in modern systematics. Total evidence is a classical principle of inductive inference and does not imply a deductive test of homology. The test of congruenceby itselfis based philosophically on a coherence theory of truth (coherentism in epistemology), which is unconcerned with empirical foundation. We therefore argue that coherence of character statements (congruence of characters) is a necessary, but not a sufficient, condition to support or refute hypotheses of homology or phylogenetic relationship. There should be at least some causal grounding for homology hypotheses beyond mere congruence. Such causal grounding may be achieved, for example, through empirical investigations of comparative anatomy, developmental biology, functional morphology and secondary structure.

© The Willi Hennig Society 2006.
The how and why of branch support and partitioned branch support, with a new index to assess partition incongruence
Authors: Brower Andrew V. Z.
Published: August 2006

An introduction and step‐by‐step guide to the calculation of branch support (BS) and partitioned branch support (PBS) is provided, along with a new summary measure of conflict among data partitions, the partition congruence index (PCI). Patterns of PCI vs. BS are compared for two data matrices from butterflies. PCI is a close mirror of BS unless BY is relatively low and there is a lot of conflict among data partitions, in which case PCI becomes negative. Some theoretical concerns relating to PBS are noted.

© The Willi Hennig Society 2006.
Report on the Ohio State University workshops in phylogenetic methods
Authors: Abdul‐Salim Kobinah , Daly Marymegan , Freudenstein John V. , Wenzel John W.
Published: August 2006

A three‐part series of workshops in phylogenetic methods was held at the Ohio State University in September and December 2005. The first two were sponsored by the OSU Mathematical Biosciences Institute (MBI), and focused on phylogeography and phylogenetic data, and phylogenetic analysis of large data sets respectively. These workshops highlighted theoretical and practical aspects of phylogeographic inferences using model‐based approaches (e.g. likelihood and Bayesian MCMC), as well as current approaches to analyzing large datasets using both parsimony and model‐based methods. The third workshop was sponsored by OSU systematics faculty, and was intended to provide practical training in current tools of phylogenetic analysis at the beginning and intermediate levels. The success of these workshops emphasizes the need for greater interaction between those involved in theoretical and empirical phylogenetic research. Further workshops, such as these, would serve to bring a practical understanding of these methods to as broad an audience as possible.

© The Willi Hennig Society 2006.
Inhibition of tumor growth by NF‐κB inhibitors
Authors: Umezawa Kazuo
Published: August 2006

NF‐κB is a transcription factor that induces inflammatory cytokines and anti‐apoptotic proteins. NF‐κB is often constitutively activated in human cancers and leukemias, which might increase the malignant character of neoplastic diseases. Therefore, NF‐κB inhibitors might be useful as anticancer agents. Our research team designed a new NF‐κB inhibitor that is based on the structure of the antibiotic epoxyquomicin C isolated from a microorganism. The designed compound, DHMEQ, inhibited the ligand‐induced activation of NF‐κB, and it also inhibited the constitutively activated NF‐κB in cancer cells. DHMEQ is a unique inhibitor of NF‐κB that acts at the level of the nuclear translocation. It inhibited both canonical and non‐canonical NF‐κB activating pathways. It inhibited various carcinomas and leukemias in animal models without any toxicity, and might be useful as an anticancer agent. (Cancer Sci 2006; 97: 990–995)
Staging performance of carbon‐11 choline positron emission tomography/computed tomography in patients with bone and soft tissue sarcoma: Comparison with conventional imaging
Authors: Tateishi Ukihide , Yamaguchi Umio , Maeda Testuo , Seki Kunihiko , Terauchi Takashi , Kawai Akira , Arai Yasuaki , Moriyama Noriyuki , Kakizoe Tadao
Published: August 2006

The present study was conducted to compare the diagnostic accuracy between carbon‐11 choline (11C‐choline) positron emission tomography (PET)/computed tomography (CT) and conventional imaging for the staging of bone and soft tissue sarcomas. Sixteen patients who underwent 11C‐choline PET/CT prior to treatment were evaluated retrospectively for staging accuracy. Conventional imaging methods consisted of 99,mTc‐hydroxymethylene diphosphonate bone scintigraphy, chest CT and magnetic resonance imaging of the primary site. The images were reviewed and a consensus was reached by two board‐certified radiologists who were unaware of any clinical or radiological information using hard‐copy films and multimodality computer platform. Tumor stage was confirmed by histological examination and/or by an obvious progression in number and/or size of the lesions on follow‐up examinations. Reviewers examining both 11C‐choline PET/CT and conventional imaging classified T stage in all patients. Interpretation based on 11C‐choline PET/CT, the Node (N) stage was correctly diagnosed in all patients, whereas the accuracy of conventional imaging in N stage was 63%. Tumor Node Metastasis (TNM) stage was assessed correctly with 11C‐choline PET/CT in 15 of 16 patients (94%) and with conventional imaging in eight of 16 patients (50%). The overall TNM staging and N staging accuracy of 11C‐choline PET/CT were significantly higher than that of conventional imaging (P < 0.05). 11C‐choline PET/CT is more accurate than conventional imaging regarding clinical staging of patients with bone and soft tissue sarcomas. A whole body 11C‐choline PET/CT might be acceptable for imaging studies of tumor staging prior to treatment. (Cancer Sci 2006; 97: 1125–1128)
Genetic instability in cancer cells by impaired cell cycle checkpoints
Authors: Nakanishi Makoto , Shimada Midori , Niida Hiroyuki
Published: August 2006

Cells continuously encounter DNA damage caused either by damaging agents, including oxygen radicals and DNA replication errors caused by stalled replication forks, or by extracellular environments such as ultraviolet or ionizing irradiation. Such DNA damage poses a great threat to genome stability, potentially leading to loss or amplification of chromosome activity, which may result in cellular senescence, cancer or apoptosis. The DNA damage checkpoints coordinate an arrest in cell cycle progression with the DNA repair process, suppressing either mitotic catastrophe or proliferation of cells with damaged DNA. Numerous key players have been identified in terms of damage sensor proteins, transducer kinases and effectors, but their coordination and interconnectedness in damage control have only recently become evident. In this review, we discuss changes in chromatin structure, recruitment of mediator proteins and activation of transducer kinases in response to DNA damage. These cellular responses are important for determining the potential effects of current cancer therapies in terms of toxicity and efficacy. (Cancer Sci 2006; 97: 984–989)
Estrogen‐mediated post transcriptional down‐regulation of P‐glycoprotein in MDR1‐transduced human breast cancer cells
Authors: Mutoh Kazuyoshi , Tsukahara Satomi , Mitsuhashi Junko , Katayama Kazuhiro , Sugimoto Yoshikazu
Published: August 2006

The human multidrug resistance gene 1 (MDR1) encodes the plasma membrane P‐glycoprotein (P‐gp/ABCB1) that functions as an efflux pump for various anticancer agents. We recently reported that estrogens down‐regulate the expression of breast cancer resistance protein (BCRP/ABCG2). In our present study we demonstrate that estrogens also down‐regulate P‐gp expression in the MDR1‐transduced, estrogen receptor α (ER‐α)‐positive human breast cancer cells, MCF‐7/MDR and T‐47D/MDR. The P‐gp expression levels in MCF‐7/MDR cells treated with 100 pM estradiol were found to be 10–20‐fold lower than the levels in these same cells that were cultured without estradiol. In contrast, estradiol did not affect the P‐gp expression levels in the ER‐α‐negative cancer cells, MDA‐MB‐231/MDR and NCI/ADR‐RES. Estrone and diethylstilbestrol were also found to down‐regulate P‐gp in MCF‐7/MDR cells, but progesterone treatment did not produce this effect. Tamoxifen reversed the estradiol‐mediated down‐regulation of P‐gp in MCF‐7/MDR cells, suggesting that ER‐α activity is necessary for the effects of estradiol upon P‐gp. However, estradiol was found not to alter the MDR1 transcript levels in either MCF‐7/MDR and T‐47D/MDR cells, suggesting that post‐transcriptional mechanisms underlie its effects upon P‐gp down‐regulation. MCF‐7/MDR cells also showed eight‐fold higher sensitivity to vincristine when treated with 100 pM estradiol, than when treated with 1 pM estradiol. These results may serve to provide a better understanding of the expression control of ABC transporters, and possibly allow for the establishment of new cancer chemotherapy strategies that would control P‐gp expression in breast cancer cells and thereby increase their sensitivity to MDR1‐related anticancer agents. (Cancer Sci 2006; 97: 1198–1204)
Effect of methotrexate treatment on expression levels of multidrug resistance protein 2, breast cancer resistance protein and organic anion transporters Oat1, Oat2 and Oat3 in rats
Authors: Shibayama Yoshihiko , Ushinohama Kazami , Ikeda Ryuji , Yoshikawa Yoshimi , Motoya Toshiro , Takeda Yasuo , Yamada Katsushi
Published: August 2006

The ATP binding cassette (ABC) transporters, multidrug resistance protein 2 (Mrp2; Abcc2) and breast cancer resistance protein (Bcrp; Abcg2), and organic anion transporters (Oats) mediate excretion of methotrexate (MTX) and many other drugs. However, it is not known whether MTX treatment leads to any changes in the expression of these transporters. We examined the effect of MTX treatment on expression of Mrp2, Bcrp and Oats in rats. MTX was single injected intraperitoneally at doses of 10, 50 and 150 mg/kg, and then Western blot analysis was performed. The levels of Mrp2, Oat1 and Oat2 on day 1 after the treatment showed no significant change. Four days after injection of 150 mg/kg MTX, the Mrp2 levels in the liver and ileum, but not in the kidney, were markedly down‐regulated to 20 ± 3.6% and 8.9 ± 3.8% (mean ± SEM) of controls, respectively. Renal Oat1 and Oat3 were also down‐regulated to 56.4 ± 4.3% (Oat1) and 54.3 ± 5.5% (Oat3) of controls. These effects of MTX were almost recovered by leucovorin which rescues normal cells from MTX toxicity. MTX treatment also decreased mRNA levels of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) to 65.5 ± 17.9% and 59.6 ± 14.5% of controls in the liver, respectively. MTX treatment has no apparent effect on expression levels of Bcrp, cytochrome P450 2B6 and 3A1. In conclusion, these data indicate that MTX treatment down‐regulates expression levels of Mrp2, Oat1 and Oat3, and its effects are recovered by leucovorin. (Cancer Sci 2006; 97: 1260–1266)
Review article: induction therapy for patients with active ulcerative colitis
Authors: TRAVIS S. P. L.
Published: August 2006

5‐aminosalicylic acid (mesalazine) is considered first‐line therapy for active mild–moderate, left‐sided or extensive ulcerative colitis. With modern delayed‐release formulations, conventional doses are very well tolerated, and there is accumulating evidence that increasing the dose, to >4 g/day, leads to higher response rates and earlier symptom relief in patients with ulcerative colitis.

There is evidence that combining oral and rectal (enema) formulations of 5‐aminosalicylic acid leads to faster and higher remission rates. Despite the fact that clinical trials in ulcerative colitis have often used different endpoints, making it difficult to make objective comparisons, the evidence now strongly suggests that it is appropriate to start patients with mild or moderately active ulcerative colitis on doses of 5‐aminosalicylic acid of at least 4 g/day.

For those with extensive disease, adding rectal 5‐aminosalicylic acid improves remission rates; the same seems likely to be true for limited disease, but robust evidence is lacking. Rectal 5‐aminosalicylic acid may in fact be sufficient on its own for patients with active proctitis. Patients with mild–moderate ulcerative colitis who do not improve within 2 weeks of high‐dose 5‐aminosalicylic acid should have treatment augmented by oral steroids.
Review article: maintenance therapy in patients with ulcerative colitis
Authors: ORCHARD T. , PROBERT C. S. , KESHAV S.
Published: August 2006

British Society of Gastroenterology guidelines recommend that all patients with ulcerative colitis should receive long‐term therapy with a 5‐aminosalicylic acid compound to maintain remission.

Recent studies have shown that time spent in remission is longer when the maintenance dose is increased from 1.2 to 2.4 g/day, with patients with extensive disease benefiting most from an increase with dosage. A retrospective analysis also found that the frequency of relapse was lower in patients taking more than the median dose of 5‐aminosalicylic acid (1.6 g/day) compared with those taking less than the median dose. Similarly, when 5‐aminosalicylic acids are used to induce remission, continuing the induction dosage for an extra 4 weeks prolongs remission and reduces the frequency of relapse. However, patients rarely comply fully with the prescribed dose regimen, which can lead to effective under‐dosing.

The recent discovery that 5‐aminosalicylic acids may act in ulcerative colitis by activating peroxisome proliferator‐activated receptor‐γ, a nuclear receptor that plays a role in the control of cell proliferation and apoptosis, has given new impetus to the idea that long‐term therapy with 5‐aminosalicylic acid may reduce the risk of colorectal cancer. Epidemiological studies are beginning to provide evidence to support this view.

Accumulating evidence suggests that the next revision of the clinical guidelines should suggest life‐long doses of 5‐aminosalicylic acid of ≥2 g/day for maintenance of remission in patients with ulcerative colitis.
Immune reconstitution after purified autologous and allogeneic blood stem cell transplantation compared with unmanipulated bone marrow transplantation in children
Authors: Schwinger Wolfgang , Weber‐Mzell Daniela , Zois Birgit , Rojacher Tanja , Benesch Martin , Lackner Herwig , Dornbusch Hans Juergen , Sovinz Petra , Moser Andrea , Lanzer Gerhard , Schauenstein Konrad , Ofner Petra , Handgretinger Rupert , Urban Christian
Published: August 2006

Immune reconstitution is critical for the long‐term success of haematopoietic stem cell transplantation (HSCT). We prospectively analysed immune reconstitution parameters after transplantation of autologous (group 1; n = 10) and allogeneic (group 2; n = 12) highly purified CD34+ peripheral blood stem cells (PBSC) and unmanipulated allogeneic bone marrow (BM) (group 3; n = 9) in children. Median follow‐up after HSCT was 56 (group 1), 61 (group 2), and 40·5 months (group 3). Median CD34‐cell dose transplanted in the three groups was 9·4 × 106/kg, 20·3 × 106/kg, and 4·25 × 106/kg recipient's body weight (BW) respectively. Complete haematopoietic engraftment was seen in all patients without any significant differences between the three groups. T‐cell reconstitution at 6 months was significantly delayed in autologous peripheral blood stem cell transplantation (PBSCT) compared with allogeneic BM transplantation (P < 0·028) and allogeneic PBSCT (P < 0·034). At 3 months after transplantation numbers of CD56+/3− natural killer cells were higher in the allogeneic PBSC group (P < 0·01) compared with the BM group. The numbers of proven bacterial and viral infections were equally distributed between the three groups. In conclusion, recipients of allogeneic highly purified CD34+ PBSC or unmanipulated BM have higher lymphocyte subset counts at 6 months after transplantation than recipients of autologous CD34‐selected PBSC. Infection rates and outcome, however, were not significantly different.
Reversal of immune thrombocytopenia in mice by cross‐linking human immunoglobulin G with a high‐affinity monoclonal antibody
Authors: Bazin Renée , Lemieux Réal , Tremblay Tony
Published: August 2006

Intravenous immunoglobulins (IVIgs) are used to treat an increasing number of autoimmune diseases, but their exact mechanism of action remains unknown. This study showed that cross‐linking of human IgG present in IVIg preparations using a mouse monoclonal anti‐human IgG generated complexes that prevented or reversed thrombocytopenia in mice more efficiently than IVIg. Furthermore, biologically active complexes were obtained simply by adding the monoclonal antibody to human serum. These results suggest the possible development of an IVIg‐free substitute through the ex vivo, and possibly in vivo, formation of immune complexes containing autologous IgG of immune thrombocytopenic purpura patients.
The heat shock protein 90 inhibitor 17‐AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt, Bid and activating caspase 9
Authors: Georgakis Georgios V. , Li Yang , Younes Anas
Published: August 2006

Mantle cell lymphoma (MCL), a distinct type of non‐Hodgkin lymphoma, is characterised by the overexpression of cyclin D1. Heat shock protein 90 (HSP90) is a molecular chaperon to proteins that regulate cell cycle and survival. 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG), a HSP90 small molecule inhibitor, induced G0/1 cell cycle arrest and cell death in a dose‐ and time‐dependent manner in MCL cell lines. This effect was associated with the downregulation of cyclin D1, cdk4 and Akt, depletion of Bid, and activation of the intrinsic/mitochondrial caspase pathway. These data suggest that 17‐AAG may have a potential therapeutic value in patients with MCL.
Inherited and de novo von Willebrand disease ‘Vicenza’ in UK families with the R1205H mutation: diagnostic pitfalls and new insights
Authors: Lester William A. , Guilliatt Andrea M. , Surdhar Gurcharan K. , Enayat Said M. , Wilde Jonathan T. , Willoughby Sara , Grundy Pam , Cumming Anthony M. , Collins Peter W. , Hill Frank G. H.
Published: August 2006

von Willebrand disease (VWD) caused by the R1205H mutation has distinct and reproducible clinical and laboratory features. This report describes the phenotypic and molecular investigation of seven kindreds with VWD Vicenza R1205H. All affected individuals have historically been diagnosed with moderate to severe type 1 VWD. Amongst all families with highly penetrant type 1 VWD investigated at our centre, heterozygosity for the R1205H mutation was found to be the most common underlying molecular defect. A severe laboratory phenotype associated with a bleeding history that was milder than expected was commonly observed, consistent with previous published case reports; however, abnormal ultralarge high molecular weight multimers were not detected in resting plasma samples. We also provide evidence that the R1205H mutation may arise de novo– evidence that a common genetic origin for this mutation is unlikely.
The evolution towards ambulatory and day‐case management of febrile neutropenia
Authors: Chisholm Julia C. , Dommett Rachel
Published: August 2006

Febrile neutropenia (FN) is only second to chemotherapy administration as a cause of hospital admission during treatment for cancer. As FN may signify serious or life‐threatening infection, management protocols have focussed on trying to prevent adverse outcomes in these patients. However, it is now possible to identify a subset of patients with FN at low risk of life‐threatening complications in whom duration of hospitalisation and intensity of therapy can be reduced safely. This review discusses how the management of FN has evolved to enable patients identified as low risk to be treated on specific low risk management strategies, with an emphasis on some of the practical considerations for the implementation of such strategies.
Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells
Authors: Raje N. , Kumar S. , Hideshima T. , Ishitsuka K. , Yasui H. , Chhetri S. , Vallet S. , Vonescu E. , Shiraishi N. , Kiziltepe T. , Elford H.L. , Munshi N.C. , Anderson K.C.
Published: August 2006

Ribonucleotide reductase (RR) is the enzyme that catalyses the rate‐limiting step in DNA synthesis, the production of deoxynucleotides. RR activity is markedly elevated in tumour tissue and is crucial for cell division. It is therefore an excellent target for cancer chemotherapy. This study examined the anti‐myeloma activity of Didox (3,4‐Dihydroxybenzohydroxamic acid), a novel RR inhibitor (RRI). Our data showed that Didox induced caspase‐dependent multiple myeloma (MM) cell apoptosis. Didox, unlike other RRIs that mainly target the pyrimidine metabolism pathway, targets both purine and pyrimidine metabolism pathways in MM, as demonstrated by transcriptional profiling using the Affymetrix U133A 2·0 gene chip. Specifically, a ≥2‐fold downregulation of genes in these anabolic pathways was shown as early as 12 h after exposure to Didox. Furthermore, apoptosis was accompanied by downregulation of bcl family proteins including bcl‐2, bclxl, and XIAP. Importantly, RR M1 component transcript was also downregulated, associated with decreased protein expression. Genes involved in DNA repair mechanisms, specifically RAD 51 homologue, were also downregulated. As Didox acts on MM cells by inhibiting DNA synthesis and repair, combination studies with melphalan, an agent commonly used in MM, were performed. A strong in vitro synergism was shown, with combination indices of <0·7 as determined by the Chou–Talalay method. These studies therefore provide the preclinical rationale for evaluation of Didox, alone and in combination with DNA‐damaging agents, to improve patient outcome in MM.
The use of intermediate purity factor VIII concentrate BPL 8Y as prophylaxis and treatment in congenital thrombotic thrombocytopenic purpura
Authors: Scully Marie , Gattens Michael , Khair Kate , Liesner Ri
Published: August 2006

This report presents seven children with congenital thrombotic thrombocytopenic purpura (TTP). Six had a history of severe neonatal unconjugated hyperbilirubinaemia and thrombocytopenia. The seventh child had no neonatal problems but has suffered three episodes of acute TTP. The subsequent clinical course of the children varied. Five had a relapsing–remitting course and one had chronic microangiopathic haemolytic anaemia. The five oldest children initially received plasma infusions but, because of viral safety issues and easier administration, they now receive intermediate purity US‐sourced plasma‐derived factor VIII concentrate: BPL 8Y. Effective prophylaxis and treatment is possible in congenital TTP using BPL 8Y.