bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient‐reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy
Authors: Elting Linda S. , Keefe Dorothy M. , Sonis Stephen T. , Garden Adam S. , Spijkervet F. K. L. , Barasch Andrei , Tishler Roy B. , Canty Thomas P. , Kudrimoti Mahesh K. , Vera‐Llonch Montserrat ,   for the Burden of Illness Head and Neck Writing Committee
Published: October 2008

BACKGROUND.

The risk, severity, and patient‐reported outcomes of radiation‐induced mucositis among head and neck cancer patients were prospectively estimated.

METHODS.

A validated, patient‐reported questionnaire (OMDQ), the FACT quality of life (QOL), and the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scales were used to measure mucositis (reported as mouth and throat soreness), daily functioning, and use of analgesics. Patients were studied before radiotherapy (RT), daily during RT, and for 4 weeks after RT.

RESULTS.

Contrary to previous reports, the risk of mucositis was virtually identical in the 126 patients with oral cavity or oropharynx tumors (99% overall; 85% grade 3‐4) compared with 65 patients with tumors of the larynx or hypopharynx (98% overall; 77% grade 3‐4). The mean QOL score decreased significantly during RT, from 85.1 at baseline to 69.0 at Week 6, corresponding with the peak of mucositis severity. The mean functional status score decreased by 33% from 18.3 at baseline to 12.3 at Week 6. The impact of mucositis on QOL was proportional to its severity, although even a score of 1 or 2 (mild or moderate) was associated with a significant reduction in QOL (from 93.6 at baseline to 74.7 at Week 6). Despite increases in analgesic use from 34% at baseline to 80% at Week 6, mean mucositis scores exceeded 2.5 at Week 6.

CONCLUSIONS.

Mucositis occurs among virtually all patients who are undergoing radiation treatment of head and neck cancers. The detrimental effects on QOL and functional status are significant, and opioid analgesia provides inadequate relief. Preventive rather than symptom palliation measures are needed. Cancer 2008. © 2008 American Cancer Society.
Sustained delivery of NT‐3 from lens fiber cells in transgenic mice reveals specificity of neuroprotection in retinal degenerations
Authors: LaVail Matthew M. , Nishikawa Shimpei , Duncan Jacque L. , Yang Haidong , Matthes Michael T. , Yasumura Douglas , Vollrath Douglas , Overbeek Paul A. , Ash John D. , Robinson Michael L.
Published: October 2008

Several neurotrophic factors (NTFs) are effective in protecting retinal photoreceptor cells from the damaging effects of constant light and slowing the rate of inherited photoreceptor degenerations. It is currently unclear whether, if continuously available, all NTFs can be protective for many or most retinal degenerations (RDs). We used transgenic mice that continuously overexpress the neurotrophin NT‐3 from lens fibers under the control of the αA‐crystallin promoter to test for neuroprotection in light‐damage experiments and in four naturally occurring or transgenically induced RDs in mice. Lens‐specific expression of NT‐3 mRNA was demonstrated both by in situ hybridization in embryos and by reverse‐transcriptase polymerase chain reaction (RT‐PCR) in adult mice. Furthermore, NT‐3 protein was found in abundance in the lens, ocular fluids, and retina by enzyme‐linked immunosorbent assay (ELISA) and immunocytochemistry. Overexpression of NT‐3 had no adverse effects on the structure or function of the retina for up to at least 14 months of age. Mice expressing the NT‐3 transgene were protected from the damaging effects of constant light to a much greater degree than those receiving bolus injections of NT‐3. When the NT‐3 transgene was transferred into rd/rd, Rds/+, Q344ter mutant rhodopsin or Mertk knockout mice, overexpression of NT‐3 had no protective effect on the RDs in these mice. Thus, specificity of the neuroprotective effect of NT‐3 is clearly demonstrated, and different molecular mechanisms are inferred to mediate the protective effect in light‐induced and inherited RDs. J. Comp. Neurol. 511:724–735, 2008. © 2008 Wiley‐Liss, Inc.
Cervical prephrenic interneurons in the normal and lesioned spinal cord of the adult rat
Authors: Lane Michael A. , White Todd E. , Coutts Marcella A. , Jones Alex L. , Sandhu Milapjit S. , Bloom David C. , Bolser Donald C. , Yates Bill J. , Fuller David D. , Reier Paul J.
Published: October 2008

Although monosynaptic bulbospinal projections to phrenic motoneurons have been extensively described, little is known about the organization of phrenic premotor neurons in the adult rat spinal cord. Because interneurons may play an important role in normal breathing and recovery following spinal cord injury, the present study has used anterograde and transneuronal retrograde tracing to study their distribution and synaptic relations. Exclusive unilateral, first‐order labeling of the phrenic motoneuron pool with pseudorabies virus demonstrated a substantial number of second‐order, bilaterally distributed cervical interneurons predominantly in the dorsal horn and around the central canal. Combined transneuronal and anterograde tracing revealed ventral respiratory column projections to prephrenic interneurons, suggesting that some propriospinal relays exist between medullary neurons and the phrenic nucleus. Dual‐labeling studies with pseudorabies virus recombinants also showed prephrenic interneurons integrated with either contralateral phrenic or intercostal motoneuron pools. The stability of interneuronal pseudorabies virus labeling patterns following lateral cervical hemisection was then addressed. Except for fewer infected contralateral interneurons at the level of the central canal, the number and distribution of phrenic‐associated interneurons was not significantly altered 2 weeks posthemisection (i.e., the point at which the earliest postinjury recovery of phrenic activity has been reported). These results demonstrate a heterogeneous population of phrenic‐related interneurons. Their connectivity and relative stability after cervical hemisection raise speculation for potentially diverse roles in modulating phrenic function normally and postinjury. J. Comp. Neurol. 511:692–709, 2008. © 2008 Wiley‐Liss, Inc.
Comparative analysis of cadherin expression and connectivity patterns in the cerebellar system of ferret and mouse
Authors: Neudert Franziska , Krishna‐K.  , Nuernberger Monique , Redies Christoph
Published: October 2008

The cerebellum shows remarkable variations in the relative size of its divisions among vertebrate species. In the present study, we compare the cerebella of two mammals (ferret and mouse) by mapping the expression of three cadherins (cadherin‐8, protocadherin‐7, and protocadherin‐10) at similar postnatal stages. The three cadherins are expressed differentially in parasagittal stripes in the cerebellar cortex, in the portions of the deep cerebellar nuclei, in the divisions of the inferior olivary nucleus, and in the lateral vestibular nucleus. The expression profiles suggest that the cadherin‐positive structures are interconnected. The expression patterns resemble each other in ferret and mouse, although some differences can be observed. The general resemblance indicates that cerebellar organization is based on a common set of embryonic divisions in the two species. Consequently, the large differences in cerebellar morphology between the two species are more likely caused by differential growth of these embryonic divisions than by differences in early embryonic patterning. Based on the cadherin expression patterns, a model of corticonuclear projection territories in ferret and mouse is proposed. In summary, our results indicate that the cerebellar systems of rodents and carnivores display a relatively large degree of similarity in their molecular and functional organization. J. Comp. Neurol. 511:736–752, 2008. © 2008 Wiley‐Liss, Inc.
Acetylcholine innervation of the adult rat thalamus: Distribution and ultrastructural features in dorsolateral geniculate, parafascicular, and reticular thalamic nuclei
Authors: Parent Martin , Descarries Laurent
Published: October 2008

The acetylcholine (ACh) innervation of thalamus arises mainly from the brainstem pedunculopontine and laterodorsal tegmental nuclei. By using immunocytochemistry with a monoclonal antibody against whole rat choline acetyltransferase (ChAT), we quantified the distribution and characterized the ultrastructural features of these nerve terminals (axon varicosities) in the dorsolateral geniculate (DLG), parafascicular (PF), and reticular thalamic (Rt) nuclei of adult rat. The regional density of ACh innervation was the highest in PF (2.1 × 106 varicosities/mm3), followed by Rt (1.7 × 106) and DLG (1.3 × 106). In single thin sections, ChAT‐immunostained varicosity profiles appeared comparable in shape and content in the three nuclei, but significantly larger in PF than in DLG and Rt. The number of these profiles displaying a synaptic junction was also much higher in PF than in DLG and Rt, indicating that all ChAT‐immunostained varicosities in PF were synaptic, but only 39% in DLG and 33% in Rt. The hypothesis that glutamate corelease might account for the maintenance of the entirely synaptic ACh innervation in PF was refuted by the lack of colocalization of ChAT and vesicular glutamate transporter 2 (VGLUT2) in PF axon varicosities after dual immunolabeling. These data suggest that diffuse as well as synaptic transmission convey modulatory effects of the ACh input from brainstem to DLG and Rt during waking. In contrast, the entirely synaptic ACh input to PF should allow for a direct relaying of the information from brainstem, affecting basal ganglia function as well as perceptual awareness, including attention and pain perception. J. Comp. Neurol. 511:678–691, 2008. © 2008 Wiley‐Liss, Inc.
Types of taste circuits synaptically linked to a few geniculate ganglion neurons
Authors: Zaidi Faisal N. , Todd Krista , Enquist Lynn , Whitehead Mark C.
Published: October 2008

The present study evaluates the central circuits that are synaptically engaged by very small subsets of the total population of geniculate ganglion cells to test the hypothesis that taste ganglion cells are heterogeneous in terms of their central connections. We used transsynaptic anterograde pseudorabies virus labeling of fungiform taste papillae to infect single or small numbers of geniculate ganglion cells, together with the central neurons with which they connect, to define differential patterns of synaptically linked neurons in the taste pathway. Labeled brain cells were localized within known gustatory regions, including the rostral central subdivision (RC) of the nucleus of the solitary tract (NST), the principal site where geniculate axons synapse, and the site containing most of the cells that project to the parabrachial nucleus (PBN) of the pons. Cells were also located in the rostral lateral NST subdivision (RL), a site of trigeminal and sparse geniculate input, and the ventral NST (V) and medullary reticular formation (RF), a caudal brainstem pathway leading to reflexive oromotor functions. Comparisons among cases, each with a random, very small subset of labeled geniculate neurons, revealed “types” of central neural circuits consistent with a differential engagement of either the ascending or the local, intramedullary pathway by different classes of ganglion cells. We conclude that taste ganglion cells are heterogeneous in terms of their central connectivity, some engaging, predominantly, the ascending “lemniscal,” taste pathway, a circuit associated with higher order discriminative and homeostatic functions, others engaging the “local,” intramedullary “reflex” circuit that mediates ingestion and rejection oromotor behaviors. J. Comp. Neurol. 511:753–772, 2008. © 2008 Wiley‐Liss, Inc.
Limited intravascular coupling in the rodent brainstem and retina supports a role for glia in regional blood flow
Authors: Kuo Ivana Y. , Chan‐Ling Tailoi , Wojcikiewicz Richard J. , Hill Caryl E.
Published: October 2008

Regional synaptic activity induces local increases in perfusion that are coupled to upstream vasodilation and improved blood flow. In the cerebral circulation, it has been proposed that astrocytes mediate the link between the initiating stimulus and local vasodilation through propagated intracellular calcium waves. In the systemic circulation the mechanism by which local vasodilation triggers upstream alterations in blood flow involves electrotonic propagation of hyperpolarization via endothelial gap junctions, although less is known concerning the cerebral circulation. The present study aimed to investigate the extent of coupling in microvessels of the rodent brainstem and retina and the subtypes of intracellular calcium stores that might mediate astrocytic signaling. Within the brainstem, connexins (Cxs) 37 and 40 were restricted to the endothelium of pial vessels and larger penetrating arterioles, whereas astrocytic Cxs30 and 43 were found closely associated with pre‐ and postsynaptic neurons and nearby microvessels. Within the rat retina, Cxs37 and 40 were expressed in large radiating arterioles, but were not found in smaller vessels on the retinal surface or in the deeper retinal layers. These Cxs were absent from all retinal vessels in mice. Astrocytes, expressing Cxs30 and 43 in the rat, but only Cx43 in the mouse, were found closely associated with superficial, but not deeper blood vessels. Inositol‐trisphosphate receptors (IP3R) 1 and 2 were expressed within brainstem astrocytes, whereas IP3R1 and 3 were expressed within retinal astrocytes. Limited intravascular coupling and the proximity of astrocytic networks to blood vessels supports a role for glia in activity‐dependent alterations in central blood flow. J. Comp. Neurol. 511:773–787, 2008. © 2008 Wiley‐Liss, Inc.
Spatiotemporal characteristics of astroglial death in the rat hippocampo‐entorhinal complex following pilocarpine‐induced status epilepticus
Authors: Kim Duk‐Soo , Kim Ji‐Eun , Kwak Sung‐Eun , Choi Kyung‐Chan , Kim Dae‐Won , Kwon Oh‐Shin , Choi Soo‐Young , Kang Tae‐Cheon
Published: October 2008

Astroglial reactive gliosis in the rat hippocampus at 8 weeks after pilocarpine‐induced status epilepticus. GFAP (red) positive reactive astrocytes in the stratum lacunosum‐moleculare show strong GS (green) immunoreactivity, while GFAP‐positive astrocytes show no GS immunoreactivity in the molecular layer of the dentate gyrus. Blue is DAPI counterstaining. J. Comp. Neurol. 511:581–598, 2008. © 2008 Wiley‐Liss, Inc.
Contralateral projections of the rat anterior olfactory nucleus
Authors: Illig Kurt R. , Eudy Jennifer D.
Published: October 2008

The anterior olfactory nucleus (AON) is a central olfactory cortical structure that has heavy reciprocal connections with both the olfactory bulb (OB) and piriform cortex. While it has been firmly established that the AON is a primary source of bilateral projections in the olfactory system through extensive connections with both the ipsilateral and contralateral OB, AON, and piriform cortex, few studies have examined this circuitry in detail. In the present study we used small injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA‐L) and the retrograde tracer FluoroGold in specific subregions of the AON to explore the topography of the interconnections between the left and right AONs. Labeled fibers were found in the contralateral AON following injections in all areas. However, detailed quantitative analyses revealed that different regions of the AON have distinct patterns of interhemispheric innervation; contralateral fibers were most heavily targeted to dorsal and lateral AON subregions, while the medial and ventral areas received relatively light projections. These results demonstrate important features of the interhemispheric circuitry of the AON and suggest separate functional roles for subregions of the AON in olfactory information processing. J. Comp. Neurol. 512:115–123, 2009. © 2008 Wiley‐Liss, Inc.
Percolation for the vacant set of random interlacements
Authors: Sidoravicius Vladas , Sznitman Alain‐Sol
Published: October 2008

We investigate random interlacements on ℤd, d ≥ 3. This model, recently introduced in [8], corresponds to a Poisson cloud on the space of doubly infinite trajectories modulo time shift tending to infinity at positive and negative infinite times. A nonnegative parameter u measures how many trajectories enter the picture. Our main interest lies in the percolative properties of the vacant set left by random interlacements at level u. We show that for all d ≥ 3 the vacant set at level u percolates when u is small. This solves an open problem of [8], where this fact has only been established when d ≥ 7. It also completes the proof of the nondegeneracy in all dimensions d ≥ 3 of the critical parameter u* of [8]. © 2008 Wiley Periodicals, Inc.
Fetal size in mid‐ and late pregnancy is related to infant alertness: The generation R study
Authors: Henrichs Jens , Schenk Jacqueline J. , Schmidt Henk G. , Arends Lidia R. , Steegers Eric A.P. , Hofman Albert , Jaddoe Vincent W.V. , Verhulst Frank C. , Tiemeier Henning
Published: October 2008

The vulnerability for behavioral problems is partly shaped in fetal life. Numerous studies have related indicators of intrauterine growth, for example, birth weight and body size, to behavioral development. We investigated whether fetal size in mid‐ and late pregnancy is related to infant irritability and alertness. In a population‐based birth cohort of 4,255 singleton full‐term infants ultrasound measurements of fetal head and abdominal circumference in mid‐ and late pregnancy were performed. Infant irritability and alertness scores were obtained by the Mother and Baby Scales at 3 months and z‐standardized. Multiple linear regression analyses revealed curvilinear associations (inverted J‐shape) of measures of fetal size in both mid‐ and late pregnancy with infant alertness. Fetal size characteristics were not associated with infant irritability. These results suggest that alterations of intrauterine growth affecting infant alertness are already detectable from mid‐pregnancy onwards. © 2008 Wiley Periodicals, Inc. Dev Psychobiol 51: 119–130, 2009
Poor in vitro induction of FOXP3 and ICOS in type 1 cytokine environment activated T‐cells from children with type 1 diabetes
Authors: Honkanen Jarno , Skarsvik Susanne , Knip Mikael , Vaarala Outi
Published: October 2008

Background

Type 1 diabetes (T1D) is characterised by loss of tolerance to beta‐cell antigens, and the insulin‐producing beta‐cells in the pancreatic islets are destroyed by the host's own immune system. Immunological risk factors associated with T1D are related to the defects in the polarization of T‐cells and in the function of regulatory T (Treg)‐cells. We set out to study whether an impaired induction of regulatory mechanisms during the generation of T‐cell responses upon stimulation is associated with T1D.

Methods

Naive T‐cells were isolated from 18 children with recent T1D (0–14days from diagnosis; mean age 9.3 years), 11 children who had had T1D for at least 1 year (mean age 10.6) and 14 non‐diabetic children (mean age 8.1). CD45RA+ T‐cells were stimulated with PHA for 72 h in type 1 cytokine [interleukin (IL)‐12 and anti‐IL‐4] or type 2 cytokine (IL‐4 and anti‐IL‐12) environment. T‐cell polarization and regulation related markers were analysed by quantitative reverse transcription polymerase chain reaction (QRT‐PCR) (Th1 promoting T‐bet, Th2 promoting GATA‐3 and regulation related FOXP3, ICOS and NFATc2).

Results

Children with recently diagnosed T1D showed decreased induction of FOXP3, ICOS and NFATc2 in T‐cells activated in type 1 cytokine milieu (p = 0.007, p = 0.001, and p = 0.02), whereas no differences between the diabetic and healthy children were seen in the up‐regulation of activation markers, T‐bet and GATA‐3.

Conclusions

The poor induction of factors that mediate down‐modulation of T‐cell responses upon stimulation in type 1 cytokine environment may contribute to the development of autoreactive type 1 responses in T1D. Copyright © 2008 John Wiley & Sons, Ltd.
Surface Energetics to Assess Microbial Adhesion onto Fluidized Chromatography Adsorbents
Authors: Vennapusa R. R. , Binner S. , Cabrera R. , Fernandez‐Lahore M.
Published: October 2008

Cell‐to‐support interaction and cell‐to‐cell aggregation phenomena have been studied in a model system composed of intact yeast cells and agarose‐based chromatography adsorbent surfaces. Biomass components and beaded adsorbents were characterized by contact angle determinations with three diagnostic liquids and, complementarily, by zeta potential measurements. Such experimental characterization of the interacting surfaces has allowed the calculation of interfacial free energy of interaction in aqueous media vs. distance profiles. The extent of biomass adhesion was inferred from calculations performed assuming standard chromatographic conditions, but different adsorption modes. Several stationary support/mobile phase systems were considered, i.e., ion exchange, hydrophobic interaction, and pseudo‐affinity. The calculated interaction energy minima revealed marginal attraction between cells and cation exchangers or agarose‐matrix beads (U ≤ |10–20| kT) but strong attraction with anion exchangers (U ≥ |200–1000| kT). Other systems including hydrophobic interaction and chelating beads showed intermediate energy minimum values (U <$>\approx<$> |40–100| kT) for interaction with biological particles. However, the calculations also showed that working conditions in the presence of salt can promote cell aggregation apart from cell‐to‐support interaction. Predictions based on the application of the XDLVO approach were confirmed by independent experimental methods, e.g., biomass deposition experiments and laser diffraction spectroscopy. The understanding of biomass attachment onto chromatographic supports can help in alleviating process limitations normally encountered during direct (primary) sequestration of bioproducts.
Systematic Approach to Solvent Selection for Biphasic Systems with a Combination of COSMO‐RS and a Dynamic Modeling Tool
Authors: Peters M. , Zavrel M. , Kahlen J. , Schmidt T. , Ansorge‐Schumacher M. , Leitner W. , Büchs J. , Greiner L. , Spiess A. C.
Published: October 2008

Biphasic aqueous‐organic systems are important reaction systems for catalytic processes. This is especially true for biocatalysis where the range of accessible products can be significantly extended. In such systems, the aqueous phase is the reactive phase in which the biocatalyst is dissolved and the organic phase is nonreactive and acts as substrate reservoir and as in situ product extraction solvent. Here, the choice of the nonreactive phase is highly important for the overall performance of the system. In this contribution, a systematic approach to solvent selection for biphasic aqueous‐organic systems is presented with respect to partition coefficients. The model reaction is the stereoselective carbon‐carbon coupling of two 3,5‐dimethoxy‐benzaldehyde molecules to (R)‐3,3',5,5'‐tetramethoxy‐benzoin catalyzed by benzaldehyde lyase (EC 4.1.2.38) from Pseudomonas fluorescens. A systematic approach to solvent selection consisting of two steps is proposed: Firstly, the conductor‐like screening model for real solvents (COSMO‐RS) is used to facilitate a fast solvent screening. Since this is an ab initio approach it allows a pre‐screening without laborious experimental input. The proposed ranking of solvents, based on the ratio of partition coefficients at infinite dilution, is a sound basis for the successive steps. Secondly, a dynamic model is fitted to experimental data in order to obtain detailed and reliable results for mass transfer and partition coefficients. Therefore, the method makes efficient use of the experimental data and substantiates quantitative results with guided experiments.
Thermodynamic Constraints in Kinetic Modeling: Thermodynamic‐Kinetic Modeling in Comparison to Other Approaches
Authors: Ederer M. , Gilles E. D.
Published: October 2008

Kinetic models of reaction networks may easily violate the laws of thermodynamics and the principle of detailed balance. In large network models, the constraints that are imposed by these laws are particularly difficult to address. This hinders modeling of biochemical reaction networks. Thermodynamic‐kinetic modeling is a method that provides a thermodynamically sound and formally appealing way for deriving dynamic model equations of reaction systems. State variables of this approach are thermokinetic potentials that describe the ability of compounds to drive a reaction. A compound has a parameter called capacity, which is the ratio of its concentration and thermokinetic potential. A reaction is described by its resistance which is the ratio of the thermokinetic driving force and flux. In these aspects, the formalism is similar to the modeling formalism for electrical networks and an analogous graphical representation is possible. The thermodynamic‐kinetic modeling formalism is equivalent to the traditional kinetic modeling formalism with the exception that it is not possible to build thermodynamically infeasible models. Here, the thermodynamic‐kinetic modeling formalism is reviewed, compared to other approaches, and some of its advantages are worked out. In contrast to other approaches, thermodynamic‐kinetic modeling does not rely on an explicit enumeration of stoichiometric cycles. It is capable of describing rate laws far from equilibrium. Further, the parameterization by capacities and resistances is particularly intuitive and powerful.
Exploiting the Link between Protein Rigidity and Thermostability for Data‐Driven Protein Engineering
Authors: Radestock S. , Gohlke H.
Published: October 2008

Understanding and exploiting the relationship between microscopic structure and macroscopic stability is important for developing strategies to improve protein stability at high temperatures. The thermostability of proteins has been repeatedly linked to an enhanced structural rigidity of the folded native state. In the current study, the rigidity of protein structures from mesophilic and thermophilic organisms along a thermal unfolding trajectory is directly probed. In order to perform this, protein structures were modeled as constraint networks, and the rigidity in these networks was quantified using the Floppy Inclusion and Rigid Substructure Topography (FIRST) method. During the thermal unfolding, a phase transition was observed that defines the rigidity percolation threshold and corresponds to the folded‐unfolded transition in protein folding. Using concepts from percolation theory and network science, a higher phase transition temperature was observed for ca. two‐thirds of the proteins from thermophilic organisms compared to their mesophilic counterparts, when applied to a data set of 20 pairs of homologues. From both the analysis of the microstructure of the constraint networks and monitoring the macroscopic behavior during the thermal unfolding, direct evidence was found for the “corresponding states” concept, which states that mesophilic and thermophilic enzymes are in corresponding states of similar flexibility at their respective optimal temperature. Finally, the current approach facilitated the identification of structural features from which a destabilization of the structure originates upon thermal unfolding. These predictions show a good agreement with the experimental data. Therefore, the information might be exploited in data‐driven protein engineering by pointing to residues that should be varied to obtain a protein with higher thermostability.
Fragmentation of Fluorinated Model Compounds Exposed to Oxygen Radicals: Spin Trapping ESR Experiments and Implications for the Behaviour of Proton Exchange Membranes Used in Fuel Cells
Authors: Danilczuk M. , Coms F. D. , Schlick S.
Published: October 2008

Low‐molecular weight model compounds (MCs) for Nafion membranes used in fuel cells were exposed at 300 K to·OH radicals produced by UV irradiation of aqueous H2O2solutions. The MCs contained fluorinated and partially fluorinated groups terminated by sulphonic or carboxylic acid groups. The fragmentation process in the MCs was studied by spin trapping electron spin resonance (ESR) methods, using 5,5‐dimethylpyrroline‐N‐oxide (DMPO), N‐tert‐butyl‐α‐phenylnitrone (PBN) and 2‐methyl‐2‐nitrosopropane (MNP) as the spin traps. The objective of these experiments was to assess the effect of the type of ionic groups (sulphonic or carboxylic) and of fluorine substitution on the spin adducts detected. DMPO experiments led to the detection of spin adducts of·OH and of carbon‐centred radicals (CCRs), and allowed the determination of the·OH attack site on the ionic and/or on the protiated or fluorinated groups. CCR adducts were also detected when using PBN as a spin trap; a key point in the interpretation of the PBN results was, however, the realisation that MNP is formed during PBN exposure to UV irradiation and oxygen or other oxidants such as H2O2. Experiments with MNP as the spin trap were the most informative in terms of structural details for adducts obtained from each MC. The results allowed the identification of CCRs present as adducts, based on large hyperfine splittings (hfs) from, and the number of, interacting19F nuclei; in addition, oxygen‐centred radicals (OCRs) as MNP adducts were also identified, with much lower hfs from19F nuclei. Taken together, the results deduced by spin trapping suggest that both sulphonic acid and acetic acid groups can be attacked by·OH radicals and confirm two possible degradation mechanisms in Nafion membranes: initiated at the backbone and at the side chain.
Frequent loss of the CDKN2C (p18INK4c) gene product in pituitary adenomas
Authors: Kirsch Matthias , Mörz Michael , Pinzer Thomas , Schackert Hans Konrad , Schackert Gabriele
Published: October 2008

Genomic alterations of cyclin‐dependent kinase inhibitors have been demonstrated in a variety of tumor types including brain tumors. Among them, the cyclin‐dependent kinase inhibitor 2A (CDKN2A or p16INK4a) gene has been shown to be frequently deleted or inactivated in astrocytic tumors. The CDKN2C (p18INK4c) gene is functionally related to CDKN2A. Moreover, mice with targeted disruption of CDKN2C alone or combined CDKN2C and cyclin‐dependent kinase inhibitor 1B (CDKN1B or p27Kip1), or CDKN2C and TP53 gene disruption develop pituitary adenomas (PA) at high frequencies. The purpose of our study was to investigate genetic alterations of the CDKN2C gene by analysis of loss of heterozygosity (LOH), screening for mutations, analysis of promoter methylation, and protein expression in 38 PAs. In addition, genomic alterations and protein expression of the cell cycle genes CDKN2A and its alternatively spliced form, p14ARF, as well as the retinoblastoma RB1 gene were investigated. LOH at the CDKN2C gene locus was detected in 25% of pituitary adenomas, whereas the RB1 and CDKN2A loci were altered in only 10%. No mutations were detected within the coding regions of the CDKN2C gene. However, 39.5% of adenomas displayed CDKN2C promoter methylation. The absence of CDKN2C protein was correlated with LOH of the CDKN2C locus on chromosome 1 and with methylation of the CDKN2C promoter. This is the first report to describe that the tumor suppressor gene CDKN2C is frequently targeted by genomic alterations in pituitary adenoma. The most common genetic alteration was promoter methylation suggesting that inactivation of CDKN2C by this mechanism may play an important role in pituitary adenoma development. Additional Supporting Information may be found in the online version of this article. © 2008 Wiley‐Liss, Inc.
Construction and application of a zebrafish array comparative genomic hybridization platform
Authors: Freeman Jennifer L. , Ceol Craig , Feng Hui , Langenau David M. , Belair Cassandra , Stern Howard M. , Song Anhua , Paw Barry H. , Look A. Thomas , Zhou Yi , Zon Leonard I. , Lee Charles
Published: October 2008

The zebrafish is emerging as a prominent model system for studying the genetics of human development and disease. Genetic alterations that underlie each mutant model can exist in the form of single base changes, balanced chromosomal rearrangements, or genetic imbalances. To detect genetic imbalances in an unbiased genome‐wide fashion, array comparative genomic hybridization (CGH) can be used. We have developed a 5‐Mb resolution array CGH platform specifically for the zebrafish. This platform contains 286 bacterial artificial chromosome (BAC) clones, enriched for orthologous sequences of human oncogenes and tumor suppressor genes. Each BAC clone has been end‐sequenced and cytogenetically assigned to a specific location within the zebrafish genome, allowing for ease of integration of array CGH data with the current version of the genome assembly. This platform has been applied to three zebrafish cancer models. Significant genomic imbalances were detected in each model, identifying different regions that may potentially play a role in tumorigenesis. Hence, this platform should be a useful resource for genetic dissection of additional zebrafish developmental and disease models as well as a benchmark for future array CGH platform development. © 2008 Wiley‐Liss, Inc.
ERK5 is a target for gene amplification at 17p11 and promotes cell growth in hepatocellular carcinoma by regulating mitotic entry
Authors: Zen Keika , Yasui Kohichiroh , Nakajima Tomoaki , Zen Yoh , Zen Kan , Gen Yasuyuki , Mitsuyoshi Hironori , Minami Masahito , Mitsufuji Shoji , Tanaka Shinji , Itoh Yoshito , Nakanuma Yasuni , Taniwaki Masafumi , Arii Shigeki , Okanoue Takeshi , Yoshikawa Toshikazu
Published: October 2008

Using high‐density oligonucleotide microarrays, we investigated DNA copy‐number aberrations in cell lines derived from hepatocellular carcinomas (HCCs) and detected a novel amplification at 17p11. To identify the target of amplification at 17p11, we defined the extent of the amplicon and examined HCC cell lines for expression of all seven genes in the 750‐kb commonly amplified region. Mitogen‐activated protein kinase (MAPK) 7, which encodes extracellular‐regulated protein kinase (ERK) 5, was overexpressed in cell lines in which the gene was amplified. An increase in MAPK7 copy number was detected in 35 of 66 primary HCC tumors. Downregulation of MAPK7 by small interfering RNA suppressed the growth of SNU449 cells, the HCC cell line with the greatest amplification and overexpression of MAPK7. ERK5, phosphorylated during the G2/M phases of the cell cycle, regulated entry into mitosis in SNU449 cells. In conclusion, our results suggest that MAPK7 is likely the target of 17p11 amplification and that the ERK5 protein product of MAPK7 promotes the growth of HCC cells by regulating mitotic entry. © 2008 Wiley‐Liss, Inc.
The galanin signaling cascade is a candidate pathway regulating oncogenesis in human squamous cell carcinoma
Authors: Sugimoto Takashi , Seki Naohiko , Shimizu Satoya , Kikkawa Naoko , Tsukada Jun , Shimada Hideaki , Sasaki Keita , Hanazawa Toyoyuki , Okamoto Yoshitaka , Hata Akira
Published: October 2008

To identify putative biomarkers in squamous cell carcinoma (SCC), a survey of parallel chromosomal alterations and gene expression studies in 10 SCC cell lines were performed using array–comparative genomic hybridization (CGH) and oligo‐microarray techniques. The most frequent changes were gains of 11q13.1‐13.3 and losses of 18q12.1‐23 in SCC. Furthermore, the expression levels of the sets of genes at both these loci in SCC were measured using microarray analysis. By combining the array‐CGH with the microarray data, 10 genes at 11q13.1‐13.3 and 6 genes at 18q12.1‐23 whose expression correlated with chromosomal alterations were identified. To verify the expression levels of the identified genes, we used expression analysis data derived from our earlier study of clinical specimens. In clinical samples, six genes (GAL, GSTP1, MRPL11, MRPL21, SF3B2, and YIF1A) at 11q13.1‐13.3 and one gene (GALR1) at 18q23 showed a significant difference between normal and tumor samples. GAL, coding for the neuropeptide galanin, and GALR1, a galanin receptor, were identified as candidate genes of oncogenesis in SCC. The expression levels of GAL, GALR1, GALR2, and GALR3 were confirmed by real‐time PCR. The expression ratio between GAL and GALR1 showed a significant negative correlation. GALR1 is a G‐protein‐coupled receptor that activates GTP‐binding proteins to trigger signaling cascades such as the mitogen‐activated protein kinase pathway, and is a well‐established mitogenic pathway. This further supports the hypothesis that the genes involved in the GAL signaling cascade are candidates for regulation of oncogenesis in SCC. © 2008 Wiley‐Liss, Inc.
Discrete choice experiments for complex health‐care decisions: does hierarchical information integration offer a solution?
Authors: van Helvoort‐Postulart Debby , Dellaert Benedict G. C. , van der Weijden Trudy , von Meyenfeldt Maarten F. , Dirksen Carmen D.
Published: October 2008

This paper describes an application of hierarchical information integration (HII) discrete choice experiments. We assessed theoretical and construct validity, as well as internal consistency, to investigate whether HII can be used to investigate complex multi‐faceted health‐care decisions (objective 1). In addition, we incorporated recent advances in mixed logit modelling (objective 2). Finally, we determined the response rate and predictive ability to study the feasibility of HII to support health‐care management (objective 3). The clinical subject was the implementation of the guideline for breast cancer surgery in day care, which is a complex process that involves changes at the organizational and management levels, as well as the level of health‐care professionals and that of patients.

We found good theoretical and construct validity and satisfactory internal consistency. The proposed mixed logit model, which included repeated measures corrections and subexperiment error scale variations, also performed well. We found a poor response, but the model had satisfactory predictive ability. Therefore, we conclude that HII can be used successfully to study complex multi‐faceted health‐care decisions (objectives 1 and 2), but that the feasibility of HII to support health‐care management, in particular in challenging implementation projects, seems less favourable (objective 3). Copyright © 2008 John Wiley & Sons, Ltd.
Geomorphologic control on pollutant retardation at the groundwater–surface water interface
Authors: Smith J.W.N. , Lerner D.N.
Published: October 2008

The results of research on the pollutant retardation potential of permeable riverbed sediments in catchments with significant groundwater–surface water (GW‐SW) interaction are presented. The fraction of organic carbon and cation exchange capacity of fluvial sediments in various geomorphologic environments have been quantified. Sediments in selected reaches of the rivers Tern and Leith (UK), from the underlying Permian sandstone aquifers, and from along the length of the rivers Severn and Eden into which the Tern and Leith discharge have been investigated. Statistical analyses show significant variation in the geochemistry and pollutant retardation potential of sediments from different geomorphologic features, and between upland and lowland rivers. The sorption potential of fine‐grained sediments deposited in pools was greater than sand in runs and coarser deposits in riffles. Similarly, sediments in lowland rivers were found to have a greater retardation potential than those in upland rivers. There was generally greater retardation potential in fluvial sediments of all types than in the underlying aquifers, and in lowland rivers the fluvial sediment retardation potential greatly dominated that of the aquifer. The findings demonstrate the potential for pollutant retardation processes in riverbed sediments of sandstone catchments, and suggest that consideration of retardation processes at the groundwater–surface water interface should be included into environmental risk‐assessment studies, in order to better assess and manage the effects of contaminated groundwater discharges to rivers, particularly in lowland catchments. Copyright © 2008 John Wiley & Sons, Ltd.
The effect of climate and land use change on flow duration in the Maryland Piedmont region
Authors: Hejazi Mohamad I. , Moglen Glenn E.
Published: October 2008

This paper describes the use of a continuous streamflow model to examine the effects of climate and land use change on flow duration in six urbanizing watersheds in the Maryland Piedmont region. The hydrologic model is coupled with an optimization routine to achieve an agreement between observed and simulated streamflow. Future predictions are made for three scenarios: future climate change, land use change, and jointly varying climate and land use. Future climate is modelled using precipitation and temperature predictions for the Canadian Climate Centre (CCC) and Hadley climate models. Results show that a significant increase in temperature under the CCC climate predictions produces a decreasing trend in low flows. A significant increasing trend in precipitation under the Hadley climate predictions produces an increasing trend in peak flows. Land use change by itself, as simulated by an additional 10% increase in imperviousness (from 20·5 to 30·5%), produces no significant changes in the simulated flow durations. However, coupling the effects of land use change with climate change leads to more significant decreasing trends in low flows under the CCC climate predictions and more significant increasing trends in peak flows under Hadley climate predictions than when climate change alone is employed. These findings indicate that combined land use and climate change can result in more significant hydrologic change than either driver acting alone. Copyright © 2008 John Wiley & Sons, Ltd.
Breast cancer susceptibility alleles and ovarian cancer risk in 2 study populations
Authors: Gates Margaret A. , Tworoger Shelley S. , Terry Kathryn L. , De Vivo Immaculata , Hunter David J. , Hankinson Susan E. , Cramer Daniel W.
Published: October 2008

Recent genome‐wide scans identified several novel breast cancer risk alleles, including variants of the FGFR2, MAP3K1 and LSP1 genes, and a study of associations between these alleles and characteristics of breast cancer patients reported a borderline significant correlation between the number of FGFR2 minor alleles and family history of breast/ovarian cancer. Given these results and similarities in the etiology of breast and ovarian cancer, we examined the association between 7 novel breast cancer susceptibility alleles and epithelial ovarian cancer risk in 2 large study populations. Our analysis included 1,173 cases and 1,201 controls from a New England‐based Case–Control study and 210 cases and 603 controls from the prospective Nurses' Health Study. We used logistic regression to estimate the odds ratio (OR) for individuals heterozygous or homozygous for the minor allele at each locus, compared to individuals with the wild‐type genotype. We examined the associations separately in each population and, after testing for heterogeneity in the results, pooled the estimates using a random effects model. There was no clear association between these polymorphisms and ovarian cancer risk in either population. The pooled per allele OR for FGFR2 was 1.06 (95% confidence interval (CI) = 0.95–1.18) for rs1219648 and 1.04 (95% CI = 0.93–1.15) for rs2981582. We had more than 80% power to detect a log‐additive OR of 1.16–1.18 per allele at the alpha = 0.05 level in the pooled analysis. Our results do not provide strong support for an association between these breast cancer susceptibility alleles and epithelial ovarian cancer risk. © 2008 Wiley‐Liss, Inc.
Risk of contralateral testicular cancer among men with unilaterally undescended testis: A meta analysis
Authors: Akre Olof , Pettersson Andreas , Richiardi Lorenzo
Published: October 2008

The association between undescended testis (cryptorchidism) and testicular cancer is established, but it is not known whether the risk of testicular cancer among men with unilateral maldescent is increased in both testes, or only on the undescended side. This is a meta‐analysis of 11 case‐control studies and 1 cohort study that all assessed the risk of testicular cancer separately for the undescended and descended testis. We used fixed‐effects meta‐analysis to calculate pooled estimates and 95% confidence intervals (CIs) for the relative risk. Of 199 tumors in men with unilateral cryptorchidism, 158 (79%) were on the ipsilateral side and 41 (21%) on the contralateral side. The pooled relative risks for testicular cancer in the ipsilateral and contralateral testis were 6.33 (95% CI, 4.30 to 9.31) and 1.74 (95% CI, 1.01 to 2.98), respectively. We conclude that in 1‐sided undescended testis, the risk of testicular cancer may be increased in both testes, although to a much greater extent on the ipsilateral side. © 2008 Wiley‐Liss, Inc.
MicroRNA profiling in human medulloblastoma
Authors: Ferretti Elisabetta , De Smaele Enrico , Po Agnese , Di Marcotullio Lucia , Tosi Emanuele , Espinola Maria Salome B. , Di Rocco Concezio , Riccardi Riccardo , Giangaspero Felice , Farcomeni Alessio , Nofroni Italo , Laneve Pietro , Gioia Ubaldo , Caffarelli Elisa , Bozzoni Irene , Screpanti Isabella , Gulino Alberto
Published: October 2008

Medulloblastoma is an aggressive brain malignancy with high incidence in childhood. Current treatment approaches have limited efficacy and severe side effects. Therefore, new risk‐adapted therapeutic strategies based on molecular classification are required. MicroRNA expression analysis has emerged as a powerful tool to identify candidate molecules playing an important role in a large number of malignancies. However, no data are yet available on human primary medulloblastomas. A high throughput microRNA expression profiles was performed in human primary medulloblastoma specimens to investigate microRNA involvement in medulloblastoma carcinogenesis. We identified specific microRNA expression patterns which distinguish medulloblastoma differing in histotypes (anaplastic, classic and desmoplastic), in molecular features (ErbB2 or c‐Myc overexpressing tumors) and in disease‐risk stratification. MicroRNAs expression profile clearly differentiates medulloblastoma from either adult or fetal normal cerebellar tissues. Only a few microRNAs displayed upregulated expression, while most of them were downregulated in tumor samples, suggesting a tumor growth‐inhibitory function. This property has been addressed for miR‐9 and miR‐125a, whose rescued expression promoted medulloblastoma cell growth arrest and apoptosis while targeting the proproliferative truncated TrkC isoform. In conclusion, misregulated microRNA expression profiles characterize human medulloblastomas, and may provide potential targets for novel therapeutic strategies. © 2008 Wiley‐Liss, Inc.