bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the impact of pore fluid chemistry on the hydromechanical behaviour of clay-based sealing materials
Authors: Siddiqua Sumi , Blatz James , Siemens Greg
Published: February 2011

The results of an experimental program undertaken to evaluate the impact of pore fluid salinity on the hydromechanical performance of light and dense backfill materials are presented. Light and dense backfills are engineered barrier materials that are being examined in the Canadian concept for storage of spent fuel in a deep geological repository. The current research investigates the impact of pore fluid chemistry on the swelling, compressibility, stiffness, and hydraulic conductivity parameters of light and dense backfills that are required as material parameters for analysis and design. In these tests, pore fluid chemistry was selected to represent groundwater within potential host units including granite and limestone rock. Results show that the performance of light backfill is significantly affected by changes in pore fluid chemistry. The swell potential of light backfill decreases with increasing salinity of the solution. The hydraulic conductivity decreases with increasing effective montmorillonite dry density and specimens saturated with saline solution have higher hydraulic conductivity than those saturated with distilled water. Conversely, the behaviour of dense backfill is governed mainly by the crushed granite component and therefore changes to the pore fluid chemistry have relatively little effect. Results of dense backfill tests confirm the material performance as a sealing material.
A new parameter for classification and evaluation of railway ballast fouling
Authors: Indraratna Buddhima , Su Li-jun , Rujikiatkamjorn Cholachat
Published: February 2011

The physical condition of railway ballast should be regularly inspected and accordingly, ballast cleaning should be carried out to maintain the safe operation of a track. This paper reviews current methods commonly used for evaluating the degree of ballast fouling, and due to their limitations, a new parameter — “relative ballast fouling ratio”— is proposed. Categories of fouling based on the proposed method are derived from the particle gradation curves taken from past literature. Comparisons between these methods demonstrate that the newly proposed relative ballast fouling ratio would best represent the influence of the type and gradation of fouling material.
A computational study of the fluctional behaviour of group 14 substituted ortho-semiquinone radicals
Authors: Ingold K. U. , DiLabio Gino A.
Published: February 2011

The dynamics of the 1,4-migration of some O-substituted 3,5-di-tert-butyl-ortho-semiquinone radicals have been calculated by density-functional theory (DFT). There is very good agreement in the rate constant and Arrhenius parameters between these calculations and experimental values for migration of H, D, and the Me3Si group. For the Me3Sn group, the calculations indicate an incredibly fast migration (k293K = 2.0 × 1012 s–1), a result that is consistent with experimental data (k293K > 109 s–1). Other O-substituents examined by DFT and compared with experimental data were H3C and Me2ClSn.
Electronic structure of S-nitrosothiols from sulfur K-edge X-ray absorption spectroscopy
Authors: Martin-Diaconescu Vlad , Perepichka Inna , Bohle D. Scott , Kennepohl Pierre
Published: February 2011

Sulfur K-edge X-ray absorption spectroscopy (S K-edge XAS) was applied to investigate the electronic structure of primary and tertiary S-nitrosothiols. Our experimental data, supported by density functional calculations, indicate that changes at Cα affect the S-nitroso group through both inductive and direct orbital effects. Furthermore, our data are consistent with a weakening of the S–N bond in tertiary S-nitrosothiols as compared to their primary S-nitroso analogues. These results support existing computational models and suggest that the reactivity of S-nitrosothiols is not dominated by the electronics of the S–N bond.
Insights into the effect of ketylimine, aldimine, and vinylene group attachment and regiosubstitution on the fluorescence deactivation of fluorene
Authors: Dufresne Stéphane , Skalski Thomas , Skene W. G.
Published: February 2011

The spectroscopic and electrochemical properties of a 9-substituted fluorene ketylimine (3) were investigated and compared with those of its vinylene analogue (4) to determine the origins of the quenched fluorescence of these compounds. The predominate mode of singlet excited state deactivation of the heteroatomic fluorene was found to be internal conversion involving bond rotation. Meanwhile, its carbon counterpart was found to undergo deactivation preferentially by intersystem crossing to form its triplet, which was confirmed by laser flash photolysis. Both 3 and 4 quenched the fluorescence of fluorene with diffusion-controlled rate constants, implying that the singlet excited states of 3 and 4 are also quenched by intramolecular photoinduced electron transfer (PET). This deactivation mode was found to be exergonically favorable (–90 kJ/mol for 3 and –81 kJ/mol for 4) according to the Rehm–Weller equation. The position of the heteroatomic bond on the fluorene moiety was further found to influence the singlet excited state deactivation pathway. The 2-substituted regioisomer decayed predominately by intramolecular PET and its fluorescence can be restored by acid protonation. Conversely, the PET mechanism is a minor deactivation mode for the 9-substituted fluorene derivative and its fluorescence can be enhanced by suppressing bond rotational modes, possible at low temperature and potentially in thin films.
Luminescence studies of copper(I)-containing [2]pseudorotaxanes
Authors: Briggs Breeze N. , Durola Fabien , McMillin David R. , Sauvage Jean-Pierre
Published: February 2011

This report describes photoluminescence studies of copper-containing [2]pseudorotaxanes that mimic elements of functioning molecular machines. Excitation with visible light induces a formal oxidation of the metal center and simulates an actuation process. In all four [2]pseudorotaxanes studied, the ring ligand is the same, but the thread ligand is variable, namely 2,9-di(anisol-4-yl)-1,10-phenanthroline (dap), 6,6′-di(anisol-4-yl)-2,2′-bipyridine (o-dabipy), 5,5′-di(anisol-4-yl)-2,2′-bipyridine (m-dabipy), or 8,8′-di(anisol-4-yl)-3,3′-bi-isoquinoline (dabiiq). The absorbance bandshapes suggest that aryl substituents extending from the core ligands engage in stacking interactions and induce a partially flattened structure in the ground state. More severe flattening occurs in the excited state and precludes the observation of emission if inter-ligand steric forces do not limit the distortion. Thus, the [2]pseudorotaxanes containing dap or o-dabipy as the thread ligand exhibit uncorrected emission maxima at around 720 nm in room-temperature dichloromethane, while the less constrained analogues, containing dabiiq or m-dabipy, are not emissive in fluid solution and barely exhibit a signal in rigid media. In dichloromethane, the luminescence quantum yields of the dap- and o-dabipy-containing systems are 6 × 10−4 and 4 × 10−4, and the excited-state lifetimes are 98 ns and 90 ns, respectively.
Photochemistry of matrix-isolated 5-cyano-2H-pyran-2-one (δ-cyano-α-pyrone) and cyanocyclobuta-1,3-diene
Authors: Menke Jessica L. , McMahon Robert J.
Published: February 2011

Matrix-isolation photochemistry (λ > 299 nm; Ar, 10 K) of 5-cyano-2H-pyran-2-one (5, δ-cyano-α-pyrone) shows complete conversion to a mixture of several ring-opened ketene isomers (6) and a ring-closed Dewar lactone (7), as detected by infrared spectroscopy. Subsequent irradiation (λ > 200 nm) causes decarboxylation of the Dewar lactone (7) to produce cyanocyclobuta-1,3-diene (8). Continued irradiation (λ > 200 nm) results in the photodecomposition of cyanocyclobuta-1,3-diene (8) to cyanoacetylene and acetylene. 4-Cyanopyridine (10) was explored as an alternative photochemical precursor to cyanocyclobuta-1,3-diene (8). It was found, however, that 10 does not exhibit observable photochemistry under our irradiation conditions.
Determination of oxygen permeabilities in thin polymer films using quenching of upconverted fluorescence in porphyrins
Authors: Sugunan Sunish K. , Paige Matthew F. , Steer Ronald P.
Published: February 2011

Proof-of-principle is demonstrated for a method of measuring the oxygen diffusion properties of thin polymer films based on quenching of the delayed upconverted S2 fluorescence of Zn(II) meso-tetraphenylporphine (ZnTPP). Empirical oxygen diffusion coefficients and permeability coefficients for poly(vinyl alcohol) (PVA) have been computed using Stern–Volmer kinetics in the steady-state regime and a nonlinear gas solubility model in the time domain. Simplified dual-mode theory has been used to calculate crude theoretical oxygen permeability coefficients to compare with the experimental values. It is confirmed that oxygen permeability in the PVA matrix is controlled largely by the characteristics of the polymer matrix, particularly its water content and distribution.
Reverse Stern–Volmer behavior for luminescence quenching in carbon nanoparticles
Authors: Cao Li , Anilkumar Parambath , Wang Xin , Liu Jia-Hui , Sahu Sushant , Meziani Mohammed J. , Myers Ethan , Sun Ya-Ping
Published: February 2011

Photoluminescence properties of carbon nanoparticles from different treatments in various suspensions were evaluated, and the results were in general agreement with those available in the literature. An interesting observation was that the quenching of luminescence emissions in the aqueous suspended carbon nanoparticles by aliphatic amines deviated from the classical Stern–Volmer behavior in a somewhat unusual fashion, exhibiting reversed quenching (increasing luminescence intensities) at very low quencher concentrations. The implication of the observation to the mechanistic framework that may account for photoluminescence emissions in both functionalized and naked carbon nanoparticles is proposed and discussed.
Competing photodehydration and excited-state intramolecular proton transfer (ESIPT) in adamantyl derivatives of 2-phenylphenols
Authors: Basarić Nikola , Cindro Nikola , Hou Yunyan , Žabčić Ivana , Mlinarić-Majerski Kata , Wan Peter
Published: February 2011

2-Phenylphenol derivatives strategically substituted with a hydroxyadamantyl substituent were synthesized and their photochemical reactivity was investigated. Derivatives 9 and 10 undergo competitive excited-state intramolecular proton transfer (ESIPT) from the phenol to the carbon atom of the adjacent phenyl ring and formal ESPT from the phenol to the hydroxyl group coupled with dehydration. These two processes (both via S1) give rise to two classes of quinone methides (QMs) that revert to starting material or react with nucleophiles, respectively. ESIPT to carbon atoms was studied by performing photolyses in the presence of D2O, whereupon deuterium incorporation to the adjacent phenyl ring was observed ([Formula: see text] = 0.1–0.2). The competing formal ESPT and dehydration takes place with quantum yields that are an order of magnitude lower and was studied by isolation of photomethanolysis products. Derivative 8 did not undergo ESIPT to carbon atom. Owing to the presence of an intramolecular H bond, an efficient ESIPT from the phenol to the hydroxyl group coupled with dehydration gives a QM that efficiently undergoes electrocyclization (overall [Formula: see text] = 0.33), to give chroman 16. In addition, spiro[adamantane-2,9′-(4′-hydroxy)fluorene] (12) undergoes ESIPT, unlike the previously reported unreactive parent 2-hydroxyfluorene. The reactive singlet excited states of the prepared biphenyl and fluorene molecules were characterized by fluorescence spectroscopy, whereas laser flash photolysis (LFP) was performed to characterize the longer lived QM intermediates.
Dynamics of capsuleplex formed between octaacid and organic guest molecules — Photophysical techniques reveal the opening and closing of capsuleplex
Authors: Jayaraj Nithyanandhan , Jockusch Steffen , Kaanumalle Lakshmi S. , Turro N. J. , Ramamurthy V.
Published: February 2011

This manuscript is concerned with the opening and closing of a capsuleplex made up of organic guest molecules and two cavitand molecules known as octaacid (OA). The capsuleplex is loosely held together in water through weak interactions. We have investigated the opening–closing of the OA capsuleplex by monitoring the quenching of excited singlet and (or) triplet states of nine different guest molecules encapsulated within a capsule by molecular oxygen that is dissolved in water surrounding the capsule. The rate constants for oxygen quenching of the excited guest molecules were estimated by monitoring the intensity of fluorescence/phosphorescence or lifetimes of excited states of guest molecules in the presence of different concentrations of oxygen in water. Guest molecules were chosen such that one could probe the opening–closing process during a time range of 0.05 to 922 µs. We believe that the oxygen quenching constant reflects the accessibility of oxygen to the guest enclosed within the OA capsuleplex, and this in turn depends on the capsule opening–closing rate constant. Based on the quenching studies, we conclude that guests whose lifetimes are shorter than 5 µs are inaccessible to oxygen. Results presented in this report suggest that the extent and time scale for opening depends on the guest.
Strain-promoted 1,3-dipolar cycloadditions of diazo compounds with cyclooctynes
Authors: Moran Joseph , McKay Craig S. , Pezacki John Paul
Published: February 2011

Strain-promoted cycloadditions of diazo compounds with dibenzocyclooctyne proceed with second-order rate constants of >10 L mol–1 s–1 at 25 °C. These reactions display rate constants that are comparable or greater than those of the analogous reactions of nitrones or azides with cyclooctynes.
Chemoselective photochemical surface reaction — Ketene versus carbene reactivity from the photolysis of saturated monolayers of pyridyl diazoesters on single-crystal Pt
Authors: Pitters Jason L. , Adkinson Dana K. , Griffiths Keith , Norton Peter R. , Workentin Mark S.
Published: February 2011

Irradiation of saturated monolayers of 3- and 4-substituted pyridyl diazoacetates on single-crystal Pt surfaces leads to either the corresponding reactive carbene or stable ketene intermediate with the chemoselectivity determined by the position of the photoreactive substituent on the pyridyl ring, which ultimately directs the available interactions with neighboring substrates.
Distribution and reactivity of gallates toward galvinoxyl radicals in SDS micellar solutions — Effect of the alkyl chain length
Authors: Bridi Raquel , Aliaga Carolina , Aspée Alexis , Abuin Elsa , Lissi Eduardo
Published: February 2011

In this work, we have evaluated the reactivity of methyl gallate, propyl gallate, and n-octyl gallate toward galvinoxyl radicals in homogeneous solution (ethanol) and sodium dodecyl sulfate micelles. In ethanol, the rate of galvinoxyl consumption was independent of the gallate’s alkyl chain length. On the other hand, reaction rates in micelles were dependent on the length of the gallate alkyl chain. Measurements of the rate of the reaction at different pH show that, even at pH 7.0, the reaction mainly involves the monodeprotonated anionic form of the gallates. Plots of reaction rates as a function of the surfactant concentration allowed us to evaluate the distribution of the gallates (KGH) and an apparent rate constant defined by the product between the intramicellar rate constant of the anion ([Formula: see text]) and its partition constant ([Formula: see text]). The values of the increment of the apparent rate constant per methylene group in the alkyl chain strongly suggest that intramicellar rate constant values are independent of the alkyl chain length. This points to a similar intramicellar localization of the phenolate moiety in the three gallates considered.
Fluorescence studies of a series of monodisperse telechelic α,ω-dipyrenyl poly(N-isopropylacrylamide)s in ethanol and in water
Authors: Yip Jamie , Duhamel Jean , Qiu Xing Ping , Winnik Françoise M.
Published: February 2011

Steady-state and time-resolved fluorescence measurements were performed on solutions in ethanol and in water (23 °C) of a series of poly(N-isopropylacrylamide)s labeled with a pyrenyl group at each chain end (Py2-PNIPAM) and ranging in molecular weight (Mn) from 5 900 to 44 500 g·mol−1. Water and ethanol are of similar solvent quality towards the PNIPAM chain. The pyrene labels, in contrast, are soluble in ethanol but not in water. The efficiency of excimer formation for Py2-PNIPAM samples in ethanol decreased with increasing chain length, a trend typical of pyrene end-labeled polymers in good solvents. The ratio IE/IM, where IE is the Py excimer emission intensity and IM is the Py monomer emission intensity, scaled as Mn−1.4, where Mn is the number-average molecular weight of the sample. The kinetics of excimer formation were more complex for aqueous Py2-PNIPAM solutions, as a consequence of pyrene–pyrene association prior to excitation. The excimer time-dependent profiles exhibited significantly faster rise times, compared with the situation in ethanol, and they could not be fitted with the traditional Birks scheme. The results are discussed in the context of the solution properties of telechelic amphiphilic PNIPAMs and are compared with data gathered previously in studies of dipyrenyl end-labeled poly(ethylene oxides), the only other polymers soluble in water and organic solvents subjected to similar studies in the past.
A porphyrin-stabilized iridium oxide water oxidation catalyst
Authors: Sherman Benjamin D. , Pillai Smitha , Kodis Gerdenis , Bergkamp Jesse , Mallouk Thomas E. , Gust Devens , Moore Thomas A. , Moore Ana L.
Published: February 2011

Colloidal solutions of iridium oxide hydrate (IrO2·nH2O) were formed using porphyrin stabilizers bearing malonate-like functional groups at each of the four meso positions of the porphyrin ring. Cyclic voltammetry and monitoring of solution oxygen concentrations under constant applied potential demonstrated the electrochemical catalytic activity of the porphyrin–IrO2·nH2O complexes for the oxidation of water to oxygen. Quenching of the porphyrin fluorescence in the complex implies strong interaction between the porphyrin and the IrO2·nH2O. These results mark a step toward developing a porphyrin-based photoanode for use in a photoelectrochemical water-splitting cell.
Altered adrenal chromaffin cell function during experimental colitis
Authors: Lukewich Mark K. , Lomax Alan E.
Published: February 2011

The sympathetic nervous system regulates visceral function through the release of catecholamines and cotransmitters from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Previous studies have shown that norepinephrine secretion is decreased during experimental colitis due to the inhibition of voltage-gated Ca2+current ( ICa) in postganglionic sympathetic neurons. The present study examined whether colonic inflammation causes a similar impairment in depolarization-induced Ca2+influx in ACCs using the dextran sulfate sodium (DSS) model of acute colitis in mice. Alterations in ACC function during colitis were assessed using fura 2-acetoxymethyl ester Ca2+imaging techniques and perforated patch-clamp electrophysiology. In ACCs isolated from mice with DSS-induced acute colitis, the high-K+-stimulated increase in intracellular Ca2+concentration ([Ca2+]i) was significantly reduced to 74% of the response of ACCs from control mice. Acute colitis caused a 10-mV hyperpolarization of ACC resting membrane potential, without a significant effect on cellular excitability. Delayed-rectifier K+and voltage-gated Na+current densities were significantly enhanced in ACCs from mice with DSS-induced acute colitis, with peak current densities of 154 and 144% that of controls, respectively. Importantly, acute colitis significantly inhibited ICain ACCs between −25 and +20 mV. Peak ICadensity in ACCs from mice with DSS-induced acute colitis was 61% that of controls. High-K+-induced increases in [Ca2+]iwere also reduced in ACCs from mice with 2,4,6-trinitrobenzene sulfonic acid-induced acute colitis and DSS-induced chronic colitis to 68 and 78% of the control responses, respectively. Our results suggest that, during colitis, voltage-dependent Ca2+influx is impaired in ACCs. Given the importance of Ca2+signaling in exocytosis, these alterations may decrease systemic catecholamine levels, which could play an important role in inflammatory bowel disease. This is the first demonstration of aberrant ACC function during experimental colitis.
The interdependent contributions of gravitational and structural features to perfusion distribution in a multiscale model of the pulmonary circulation
Authors: Clark A. R. , Tawhai M. H. , Hoffman E. A. , Burrowes K. S.
Published: February 2011

Recent experimental and imaging studies suggest that the influence of gravity on the measured distribution of blood flow in the lung is largely through deformation of the parenchymal tissue. To study the contribution of hydrostatic effects to regional perfusion in the presence of tissue deformation, we have developed an anatomically structured computational model of the pulmonary circulation (arteries, capillaries, veins), coupled to a continuum model of tissue deformation, and including scale-appropriate fluid dynamics for blood flow in each vessel type. The model demonstrates that both structural and the multiple effects of gravity on the pulmonary circulation make a distinct contribution to the distribution of blood. It shows that postural differences in perfusion gradients can be explained by the combined effect of tissue deformation and extra-acinar blood vessel resistance to flow in the dependent tissue. However, gravitational perfusion gradients persist when the effect of tissue deformation is eliminated, highlighting the importance of the hydrostatic effects of gravity on blood distribution in the pulmonary circulation. Coupling of large- and small-scale models reveals variation in microcirculatory driving pressures within isogravitational planes due to extra-acinar vessel resistance. Variation in driving pressures is due to heterogeneous large-vessel resistance as a consequence of geometric asymmetry in the vascular trees and is amplified by the complex balance of pressures, distension, and flow at the microcirculatory level.
Emergent behavior of regional heterogeneity in the lung and its effects on respiratory impedance
Authors: Kaczka David W. , Lutchen Kenneth R. , Hantos Zoltán
Published: February 2011

The ability to maintain adequate gas exchange depends on the relatively homogeneous distribution of inhaled gas throughout the lung. Structural alterations associated with many respiratory diseases may significantly depress this function during tidal breathing. These alterations frequently occur in a heterogeneous manner due to complex, emergent interactions among the many constitutive elements of the airways and parenchyma, resulting in unique signature changes in the mechanical impedance spectrum of the lungs and total respiratory system as measured by forced oscillations techniques (FOT). When such impedance spectra are characterized by appropriate inverse models, one may obtain functional insight into derangements in global respiratory mechanics. In this review, we provide an overview of the impact of structural heterogeneity with respect to dynamic lung function. Recent studies linking functional impedance measurements to the structural heterogeneity observed in acute lung injury, asthma, and chronic obstructive pulmonary disease are highlighted, as well as current approaches for the modeling and interpretation of impedance. Finally, we discuss the potential diagnostic role of FOT in the context of therapeutic interventions.
Functional EGFR Germline Polymorphisms May Confer Risk for EGFR Somatic Mutations in Non–Small Cell Lung Cancer, with a Predominant Effect on Exon 19 Microdeletions
Authors: Liu Wanqing , He Lijun , Ramírez Jacqueline , Krishnaswamy Soundararajan , Kanteti Rajani , Wang Yi-Ching , Salgia Ravi , Ratain Mark J.
Published: February 2011

Somatic mutations in the EGFR tyrosine kinase domain play a critical role in the development and treatment of non–small cell lung cancer (NSCLC). Strong genetic influence on susceptibility to these mutations has been suggested. To identify the genetic factors conferring risk for the EGFR tyrosine kinase mutations in NSCLC, a case–control study was conducted in 141 Taiwanese NSCLC patients by focusing on three functional polymorphisms in the EGFR gene [−216G/T, intron 1 (CA)n, and R497K]. Allelic imbalance of the EGFR −216G/T polymorphism was also tested in the heterozygous patients and in the NCI-60 cancer cell lines to further verify its function. We found that the frequencies of the alleles −216T and CA-19 are significantly higher in the patients with any mutation (P = 0.032 and 0.01, respectively), in particular in those with exon 19 microdeletions (P = 0.006 and 0.033, respectively), but not in the patients with L858R mutation. The −216T allele is favored to be amplified in both tumor DNA of lung cancer patients and cancer cell lines. We conclude that the local haplotype structures across the EGFR gene may favor the development of cellular malignancies and thus significantly confer risk to the occurrence of EGFR mutations in NSCLC, particularly the exon 19 microdeletions. Cancer Res; 71(7); 2423–7. ©2011 AACR.
CD73-Deficient Mice Have Increased Antitumor Immunity and Are Resistant to Experimental Metastasis
Authors: Stagg John , Divisekera Upulie , Duret Helene , Sparwasser Tim , Teng Michele W.L. , Darcy Phillip K. , Smyth Mark J.
Published: February 2011

CD73 is a cell-surface enzyme that suppresses immune responses by producing extracellular adenosine. In this study, we employed CD73 gene-targeted mice to investigate the role of host-derived CD73 on antitumor immunity and tumor cell metastasis. We found that CD73 ablation significantly suppressed the growth of ovalbumin-expressing MC38 colon cancer, EG7 lymphoma, AT-3 mammary tumors, and B16F10 melanoma. The protective effect of CD73 deficiency on primary tumors was dependent on CD8+ T cells and associated with an increased frequency of antigen-specific CD8+ T cells in peripheral blood and tumors and increased antigen-specific IFN-γ production. Replicate studies in bone marrow chimeras established that both hematopoietic and nonhematopoietic expression of CD73 was important to promote tumor immune escape. Using adoptive reconstitution of T regulatory cell (Treg)–depleted DEREG (depletion of regulatory T cells) mice, we demonstrated that part of the protumorigenic effect of Tregs was dependent on their expression of CD73. CD73-deficient mice were also protected against pulmonary metastasis of B16F10 melanoma cells after intravenous injection. Unexpectedly, we found that the prometastatic effect of host-derived CD73 was dependent on CD73 expression on nonhematopoietic cells. CD73 expression on nonhematopoietic cells, most likely endothelial cells, was critical for promoting lung metastasis in a manner independent from immunosuppressive effects. Notably, in vivo blockade of CD73 with a selective inhibitor or anti-CD73 monoclonal antibody significantly reduced tumor growth and metastasis of CD73-negative tumors. Taken together, our findings indicate that CD73 may be targeted at multiple levels to induce anticancer effects including at the level of tumor cells, Tregs, and nonhematopoietic cells. Cancer Res; 71(8); 2892–900. ©2011 AACR.
Bortezomib Enhances the Efficacy of Fulvestrant by Amplifying the Aggregation of the Estrogen Receptor, Which Leads to a Proapoptotic Unfolded Protein Response
Authors: Ishii Yuki , Papa Luena , Bahadur Urvashi , Yue Zhenyu , Aguirre-Ghiso Julio , Shioda Toshi , Waxman Samuel , Germain Doris
Published: February 2011

Purpose: Fulvestrant is known to promote the degradation of the estrogen receptor (ER) in the nucleus. However, fulvestrant also promotes the aggregation of the newly synthesized ER in the cytoplasm. Accumulation of protein aggregates leads to cell death but this effect is limited as a result of their elimination by the proteasome. We tested whether combining fulvestrant with the proteasome inhibitor, bortezomib, could enhance the accumulation of ER aggregates and cause apoptotic cell death.

Experimental Design: The rate of aggregation of the ER was monitored in ER+ breast cancer cells lines, T47D, ZR-75.1, BT474, MDA-MB-361, MCF-7, fulvestrant resistance MCF-7, and tamoxifen-resistant T47D-cyclin D1 cells. Activation of the unfolded protein response, apoptosis, and metabolic rate were also monitored in these cell lines following treatment with fulvestrant, bortezomib, or bortezomib in combination with fulvestrant.

Results: We found that bortezomib enhances the fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking the degradation of the ER in the nucleus. Further, these aggregates activate a sustained unfolded protein response leading to apoptotic cell death. Further, we show that the combination induced tumor regression in a breast cancer mouse model of tamoxifen resistance.

Conclusions: Adding bortezomib to fulvestrant enhances its efficacy by taking advantage of the unique ability of fulvestrant to promote cytoplasmic aggregates of the ER. As this effect of fulvestrant is independent of the transcriptional activity of the ER, these results suggest that this novel combination may be effective in breast cancers that are ER+ but estrogen independent. Clin Cancer Res; 17(8); 2292–300. ©2011 AACR.
Comparison of Genomics and Functional Imaging from Canine Sarcomas Treated with Thermoradiotherapy Predicts Therapeutic Response and Identifies Combination Therapeutics
Authors: Chi Jen-Tsan , Thrall Donald E. , Jiang Chen , Snyder Stacey , Fels Diane , Landon Chelsea , McCall Linda , Lan Lan , Hauck Marlene , MacFall James R. , Viglianti Benjamin L. , Dewhirst Mark W.
Published: February 2011

Purpose: While hyperthermia is an effective adjuvant treatment to radiotherapy, we do not completely understand the nature of the response heterogeneity.

Experimental Design: We performed gene expression analysis of 22 spontaneous canine sarcomas before and after the first hyperthermia treatment administered as an adjuvant to radiotherapy. In parallel, diffusion-weighted MRI (DWI) was done prior to the treatment course and at the end of therapy.

Results: From the integrative analysis of gene expression and DWI, we identified significant correlation between tumor responses with genes involved in VEGF signaling, telomerase, DNA repair, and inflammation. The treatment-induced changes in gene expression identified 2 distinct tumor subtypes with significant differences in their gene expression and treatment response, as defined by changes in DWI. The 2 tumor subtypes could also be readily identified by pretreatment gene expression. The tumor subtypes, with stronger expression response and DWI increase, had higher levels of HSP70, POT1, and centrosomal proteins, and lower levels of CD31, vWF, and transferrin. Such differential gene expression between the 2 subtypes was used to interrogate connectivity map and identify linkages to an HSP90 inhibitor, geldanamycin. We further validated the ability of geldanamycin to enhance cell killing of human tumor cells with hyperthermia and radiotherapy in clonogenic assays.

Conclusions: To our knowledge, this is one of the first successful attempts to link changes in gene expression and functional imaging to understand the response heterogeneity and identify compounds enhancing thermoradiotherapy. This study also demonstrates the value of canine tumors to provide information generalizable to human tumors. Clin Cancer Res; 17(8); 2549–60. ©2011 AACR.
Left Thoracoabdominal Approach in Surgical Treatment of Adenocarcinoma of the Esophagogastric Junction in the Northern Henan Province of China
Authors: Li Baozhong , Guo Qingqu , Yang Haijun , Guan Jianyun , Liu Zhiqiang , Li Shoumiao , Liu Guohua , Wei Linsheng
Published: February 2011

Background: The left thoracoabdominal (LTA) approach is the conventional way to treat adenocarcinoma of the esophagogastric junction (EGJ). The study was to review the outcome of the LTA approach with adenocarcinoma of the EGJ in a single institution in China. Methods: 135 consecutive adenocarcinomas of EGJ patients who underwent surgical treatment were retrospectively analyzed; data gathered included basic information on the tumor, surgical approach, postoperative complications and survival rate. Results: LTA esophagogastrectomy was performed in all patients. No patients received allogeneic blood transfusion during the operation. Among the resective procedures, proximal gastrectomy was performed in 122 cases. The mean operation time was 150 min (90–240). R₀ resection was obtained in 120 patients (88.9%). Two patients developed respiratory failure 2 days after surgery. Contrast swallow revealed a leak at the anastomosis in 2 patients. One early anastomotic stricture was observed radiologically, and pneumonia was observed in 3 patients. The number of patients with spontaneous pneumothorax and wound infections were 3 and 5, respectively. The percentage was zero in-hospital deaths. The overall survival rates at 1 year and 2 years were 89.2 and 69%, respectively. The median survival was 27.1 months. Conclusion: LTA esophagogastrectomy has a major role in the management of adenocarcinoma of the EGJ, at least in the northern Henan Province of China.
Duplication 5q and Deletion 9p due to a t(5;9)(q34;p23) in 2 Cousins with Features of Hunter-McAlpine Syndrome and Hypothyroidism
Authors: Vásquez-Velásquez A.I. , García-Castillo H.A. , González-Mercado M.G. , Dávalos I.P. , Raca G. , Xu X. , Dwyer E. , Rivera H.
Published: February 2011

We report on 2 similarly affected cousins with a compound imbalance resulting from a familial t(5;9)(q34;p23) and entailing both an ∼17-Mb 5q terminal duplication and an ∼12-Mb 9p terminal deletion as determined by G-banding, subtelomere FISH, and aCGH. The proband’s karyotype was 46,XX,der(9)t(5;9)(q34;p23)mat.ish der(9)t(5;9)(q34;p23)(9pter–,5qter+).arr 5q34q35(163,328,000–180,629,000)×3, 9p24p23(194,000–12,664,000)×1. Her cousin had the same unbalanced karyotype inherited from his father. The clinical phenotype mainly consists of a distinct craniofacial dysmorphism featuring microcephaly, flat facies, down slanting palpebral fissures, small flat nose, long philtrum, and small mouth with thin upper lip. Additional remarkable findings were craniosynostosis of several sutures, craniolacunia and preaxial polydactyly in the proband and hypothyroidism in both subjects. The observed clinical constellation generally fits the phenotypic spectrum of the 5q distal duplication syndrome (known also as Hunter-McAlpine syndrome), except for the thyroid insufficiency which can likely be ascribed to the concurrent 9p deletion, as at least 4 other 9pter monosomic patients without chromosome 5 involvement had this hormonal disorder. The present observation further confirms the etiology of the HMS phenotype from gain of the 5q35→qter region, expands the clinical pictures of partial trisomy 5q and monosomy 9p, and provides a comprehensive list of 160 patients with 5q distal duplication.
Laparoscopic Colorectal Surgery in Patients with Prior Abdominal Surgery
Authors: Fukunaga Yosuke , Kameyama Masao , Kawasaki Masayasu , Takemura Masashi , Fujiwara Yushi
Published: February 2011

Purpose: We retrospectively investigated the impact of prior abdominal surgery on the outcome of laparoscopic colorectal surgery. Patients: Among 607 colorectal cancer patients who underwent laparoscopic surgery, 192 patients had previously undergone abdominal surgery (S group) and 415 had not (non-S group). Results: The percentage of female patients was higher in the S group than in the non-S group. The incidence of conversion to open surgery was higher in the S group (5.2%, 10/192) than in the non-S group (2.6%, 11/415), but the difference was not significant (p = 0.108). Although the mean operating time and estimated blood loss were similar in the two groups, right and transverse colectomy after prior gastrectomy and ipsilateral colectomy after prior colectomy took longer and were associated with greater blood loss. The morbidity rates of the two groups were similar (S group: 15.6%, 30/192; non-S group: 14.5%, 60/415). There were 5 intraoperative small-bowel injuries or postoperative small-bowel perforations in the S group, especially in the patients with prior gastrointestinal-tract surgery. Conclusion: Our findings suggest that there is no reason to avoid laparoscopic procedures in most patients with prior abdominal surgery despite a higher conversion rate, but caution is warranted in patients who have undergone major gastrointestinal-tract surgery.
The Chromosomal Distribution of Microsatellite Repeats in the Genome of the Wolf Fish Hoplias malabaricus, Focusing on the Sex Chromosomes
Authors: Cioffi M.B. , Kejnovsky E. , Bertollo L.A.C.
Published: February 2011

Distribution of 12 mono-, di- and tri-nucleotide microsatellites on the chromosomes of 2 karyomorphs with 2 distinct sex chromosome systems (a simple XX/XY – karyomorph B and a multiple X1X1X2X2/X1X2Y – karyomorph D) in Hoplias malabaricus, commonly referred to as wolf fish, was studied using their physical mapping with fluorescence in situ hybridization (FISH). The distribution patterns of different microsatellites along the chromosomes varied considerably. Strong hybridization signals were observed at subtelomeric and heterochromatic regions of several autosomes, with a different accumulation on the sex chromosomes. A massive accumulation was found in the heterochromatic region of the X chromosome of karyomorph B, whereas microsatellites were gathered at centromeres of both X chromosomes as well as in corresponding regions of the neo-Y chromosome in karyomorph D. Our findings are likely in agreement with models that predict the accumulation of repetitive DNA sequences in regions with very low recombination. This process is however in contrast with what was observed in multiple systems, where such a reduction might be facilitated by the chromosomal rearrangements that are directly associated with the origin of these systems.
Heterogeneity of Pericentric Inversions of the Human Y Chromosome
Authors: Knebel S. , Pasantes J.J. , Thi D.A.D. , Schaller F. , Schempp W.
Published: February 2011

Pericentric inversions of the human Y chromosome (inv(Y)) are the result of breakpoints in Yp and Yq. Whether these breakpoints occur recurrently on specific hotspots or appear at different locations along the repeat structure of the human Y chromosome is an open question. Employing FISH for a better definition and refinement of the inversion breakpoints in 9 cases of inv(Y) chromosomes, with seemingly unvarying metacentric appearance after banding analysis, unequivocally resulted in heterogeneity of the pericentric inversions of the human Y chromosome. While in all 9 inv(Y) cases the inversion breakpoints in the short arm fall in a gene-poor region of X-transposed sequences proximal to PAR1 and SRY in Yp11.2, there are clearly 3 different inversion breakpoints in the long arm. Inv(Y)-types I and II are familial cases showing inversion breakpoints that map in Yq11.23 or in Yq11.223, outside the ampliconic fertility gene cluster of DAZ and CDY in AZFc. Inv(Y)-type III shows an inversion breakpoint in Yq11.223 that splits the DAZ and CDY fertility gene-cluster in AZFc. This inversion type is representative of both familial cases and cases with spermatogenetic impairment. In a further familial case of inv(Y), with almost acrocentric morphology, the breakpoints are within the TSPY and RBMY repeat in Yp and within the heterochromatin in Yq. Therefore, the presence of specific inversion breakpoints leading to impaired fertility in certain inv(Y) cases remains an open question.
Abiotic Stress and Induced DNA Hypomethylation Cause Interphase Chromatin Structural Changes in Rice rDNA Loci
Authors: Santos A.P. , Ferreira L. , Maroco J. , Oliveira M.M.
Published: February 2011

Global climate change, i.e. higher and more variable temperatures, and a gain in soil salinity are increasing plant stress with direct consequences on crop yield and quality levels. Rice productivity is strongly affected by abiotic stress conditions. The regulation of chromatin structure in response to environmental stress is poorly understood. We investigated the interphase chromatin organization from rice plants in non-stress versus stress conditions. We have used a cytogenetic approach, based on fluorescence in situ hybridization (FISH) with 45S, 5S rDNA and centromeric probes on rice tissue sections. The abiotic stress conditions included cold, heat and mild salinity and were applied during seed germination. In contrast to cold, saline and heat stresses caused extensive decondensation of 45S rDNA chromatin and also an increase in the distance between the 2 homologous 5S rDNA loci. 5-Azacytidine (5-AC), a DNA hypomethylating drug, greatly increased 45S rDNA chromatin decondensation and interestingly was able to induce polarization of centromeres in rice interphase nuclei. The abiotic stresses tested did not perturb the spatial position of centromeres, typically with circular arrangement around the nucleolus. The results suggest a role for chromatin plasticity in a world of climate changes.
Preoperative Localisation and Surgical Management of Insulinoma: Single Centre Experience
Authors: Varma Vibha , Tariciotti Laura , Coldham Christopher , Taniere Phillipe , Buckels John A. , Bramhall Simon R.
Published: February 2011

Background: The majority of insulinomas are benign, small and intrapancreatic. Preoperative localisation is important to plan the surgical management. Methods: We retrospectively analysed our data on the preoperative imaging, type of surgery and histopathological features of the operated patients with an insulinoma from January 1993 to March 2010. Univariate and multivariate analyses were performed to detect the predictive factors for survival following surgery. Results: Forty patients were operated on for insulinoma, of which 33 were benign and 7 were malignant. The sensitivity of preoperative computed tomogram scan, magnetic resonance imaging and endoscopic ultrasound, for localising the lesions was 62, 82 and 94%, respectively. Enucleation was performed in 21 (52.5%) patients, and remaining had pancreatic resection. Hepatic resection was performed in 2 and liver transplantation in 1 patient. Morbidity and perioperative mortality was 17 (42.5%) and 1 (2.7%), respectively. The overall 5- and 10-year survival was 89 and 86.5%, respectively. The presence of metastases was found to be an independent predictor of poor survival on multivariate analysis. Conclusion: Preoperative computed tomogram/magnetic resonance imaging and endoscopic ultrasound are sensitive in localizing the majority of insulinomas. Surgery offers a good long-term survival, even in patients with malignant insulinoma.
A Thick Pancreas Is a Risk Factor for Pancreatic Fistula after a Distal Pancreatectomy: Selection of the Closure Technique according to the Thickness
Authors: Eguchi Hidetoshi , Nagano Hiroaki , Tanemura Masahiro , Takeda Yutaka , Marubashi Shigeru , Kobayashi Shogo , Wada Hiroshi , Umeshita Koji , Mori Masaki , Doki Yuichiro
Published: February 2011

Background/Aims: Hand-sewn closures or stapler closures of the pancreatic remnant after a distal pancreatectomy have commonly been employed; however, the choice of technique in each patient depending on their clinical characteristics has not been discussed. Methods: Forty-eight patients who underwent a distal pancreatectomy at Osaka University Hospital between January 2007 and October 2009 were enrolled. A hand-sewn closure was planned during the 1st period (before June 2008, 26 consecutive patients), whereas a stapler closure was planned for the 2nd period (after June 2008, 22 consecutive patients). The incidence of pancreatic fistula and the patients’ characteristics were retrospectively investigated. Results: Seven patients (27%) developed a fistula in the hand-sewn group, while 5 (23%) developed a fistula in the stapler group (p = n.s.). Using logistic regression analysis for all patients, younger age and the thickness of the pancreatic remnant were identified as independent risk factors for pancreatic fistula. In the stapler group, 50% of patients with a thick pancreas developed a pancreatic fistula, while no patients with a thin pancreas developed one. Conclusion: Thick pancreas is one of the risk factors for pancreatic fistula after a distal pancreatectomy; however, a stapler closure seems to be suitable at least for thin pancreas.
Cytotypes of Kirk’s Dik-Dik (Madoqua kirkii,Bovidae) Show Multiple Tandem Fusions
Authors: Cernohorska H. , Kubickova S. , Vahala J. , Robinson T.J. , Rubes J.
Published: February 2011

Madoqua kirkii, a miniature African antelope, is noted for extensive chromosomal variation that has been categorized in four distinct cytotypes (A–D). In this investigation, we analyzed the A cytotype (2n = 46, FN = 48) using a suite of molecular cytogenetic approaches that entailed (i) whole chromosome and subchromosomal painting by fluorescence in situ hybridization (FISH), (ii) the study of Madoqua centromeric-specific DNA derived from pooled DNA obtained from the centromeric regions of the acrocentric chromosomes, and (iii) DNA from the telomere:centromere junctions of tandemly fused chromosomes. DNA from these sources was used to probe for the persistence of interstitial satellite DNA and residual centromeric sequences in the tandem and centric fusion junctions by PCR and FISH. The analyses show centromeric sequences at two of the six tandem fusion junctions. These data, and those of hybrid specimens (A × B cytotypes) in conjunction with published information permitted an interpretation of the probable sequence of chromosomal rearrangements among the M. kirkii cytotypes. We discuss the findings in the context of chromosomal evolution in these antelopes, and the implications that these hold for ex-situ breeding programs of the species.