bluuebunny/crossref_metadata_2025 huggingface dataset:
Triblock copolymers of methyl methacrylate/N‐vinyl pyrrolidone and their hydrophilication effects on poly(vinylidene fluoride) porous membranes
Authors: Pang Dong‐Xu , Liu Wei‐Dong , Li Tong , Fang Li‐Feng , Zhu Bao‐Ku
Published: September 2010

The new amphiphilic triblock copolymers of poly(N‐vinyl pyrrolidone‐b‐methyl methacrylate‐b‐N‐vinyl pyrrolidone) (P(VP‐b‐MMA‐b‐VP)) were synthesized via a reversible addition fragmentation chain transfer polymerization route. Using these copolymers as additives in casting solutions, the porous blend membranes of poly (vinylidene fluoride) and P(VP‐b‐MMA‐b‐VP) were prepared following a typical nonsolvent induced phase separation process. The influences of P(VP‐b‐MMA‐b‐VP) on the morphologies of the blend membranes were observed by scanning electron microscopy. The chemical compositions in membrane surface layers were measured by X‐ray photoelectron measurement. Water contact angle and water flux experiments were used to evaluate the hydrophilicity and permeation properties of the blend membranes. It was found that the P(VP‐b‐MMA‐b‐VP) copolymers could be retained in membrane stably in membrane formation and application process. The copolymers could enrich in surface layer and endowed the blend membrane with efficient hydrophilicity and higher water permeation flux. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
Cross‐linking and grafting with PS of EPDM in the presence of Lewis acids
Authors: Jian‐Ping Xu , Jian‐Ding Chen , Ming‐Lian Cheng
Published: September 2010

With Lewis Acids as catalysts in melt system, the influence of kinds of Lewis Acids, dosages of catalysts on the behaviors of crosslinking and grafting of ethylene–propylene–diene rubber (EPDM) were investigated. The Lewis Acids, such as anhydrous AlCl3, FeCl3, SnCl4, could initiate the crosslinking of EPDM and the grafting between EPDM and polystyrene (PS). The carbon–carbon double bonds existing on EPDM chain were favorable to the formation of the initial carbocation in the presence of Lewis Acids. The carbocation initiated carbonium ion polymerization between the unsaturated bonds, or substituted for a proton from the phenyl in the presence of PS forming EPDM‐g‐PS copolymer. Anhydrous aluminum chloride was found to be an efficient catalyst and its initiating temperatures for crosslinking or grafting were about 110°C. The amounts of gel and the data of torques showed that there was a competition between the crosslinking‐grafting reaction and the degradation of blending components in the presence of AlCl3. The EPDM‐g‐PS copolymer served as a compatibilizer in the EPDM/PS blends and enhanced the mechanical properties. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
Investigation of temperature‐swing adsorption of aromatic compounds in water using polyampholyte gels with hydrophilic nonionic groups
Authors: Morisada Shintaro , Suzuki Hiroko , Hirokawa Yoshitsugu , Nakano Yoshio
Published: September 2010

The adsorption and desorption behaviors of bisphenol‐A in water have been studied using the temperature‐responsive polyampholyte gels composed of sodium styrene sulfate (SSS), vinylbenzyl trimethylammonium chloride (VBTA), and N,N′‐dimethylacrylamide (DMAA). The resultant behaviors of the SSS‐VBTA‐DMAA gels of three different monomer compositions are compared with those of the SSS‐VBTA gel that can adsorb bisphenol‐A at room temperature and desorb the pre‐adsorbed bisphenol‐A at higher temperature as in our previous report (Morisada et al., Adsorption 2008, 14, 621), to elucidate the effect of DMAA on the adsorption property of the polyampholyte gel. The adsorption isotherms, which were described by Henry's law, indicated that the adsorption amounts of bisphenol‐A onto the SSS‐VBTA‐DMAA gels at 298 K are much larger than those at 353 K. At 298 K, the Henry's adsorption constant for the SSS‐VBTA‐DMAA gel with the lowest mole fraction of DMAA was larger than that for the SSS‐VBTA gel, whereas a further increase in the DMAA mole fraction resulted in a decrease in the adsorption constant. Moreover, the temperature‐swing adsorption experiments demonstrated that the SSS‐VBTA‐DMAA gel can repeatedly adsorb bisphenol‐A at 298 K and desorb some of the pre‐adsorbed bisphenol‐A at 353 K, where the desorption amount of bisphenol‐A is larger than that from the SSS‐VBTA gel. The results obtained here show that the addition of DMAA to the SSS‐VBTA gel slightly improves the performance of the gel as a temperature‐responsive adsorbent. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
Process‐induced monomer on a medical‐grade polymer and its effect on short‐term hydrolytic degradation
Authors: Ellä Ville , Nikkola Lila , Kellomäki Minna
Published: September 2010

While melt‐spinning biodegradable poly‐(L/D)LA 96/4 lactides into fibers, we intentionally induced monomer into the material by thermal degradation. Elevated temperatures and variable residence times were used during processing. By increasing the residence time, the molecular weight decreased, and the amount of monomer increased exponentially. The studied processing parameters induced from 0.17 to 1.24% of monomer into PLA fibers. In short‐term (9‐week) in vitro studies, the rate of degradation was significantly faster for fibers with higher amounts of monomer. After 9 weeks in vitro, the 0.17% monomer fiber lost 3% of its strength, whereas the 1.24% monomer fiber lost 65%. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Thermoset lactic acid‐based resin as a matrix for flax fibers
Authors: Åkesson Dan , Skrifvars Mikael , Seppälä Jukka , Turunen Minna
Published: September 2010

Thermoset composites were produced from flax fibers and a novel lactic acid (LA)‐based thermoset resin. This resin is based on methacrylated, star‐shaped oligomers of LA. The main purpose of this work was to evaluate whether this resin can be used to produce structural composites from flax fibers. Composites were prepared by spray impregnation followed by compression molding at elevated temperature. The tests showed that composites can be produced with as much as 70 wt% fiber. The composites were evaluated by tensile testing, flexural testing, charpy impact test, dynamic mechanical thermal analysis (DMTA), and low‐vacuum scanning electron microscopy. The ageing properties in high humid conditions were evaluated, the Young's modulus ranged from 3 GPa to 9 GPa in the best case. This work shows that structural composites can be produced from renewable material. It is clear from the results that these composites have properties that make them suitable for furniture, panels, or automotive parts. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Morphologic study of steady state electrospun polyamide 6 nanofibres
Authors: De Vrieze Sander , De Schoenmaker Bert , Ceylan Özgür , Depuydt Jara , Van Landuyt Lieve , Rahier Hubert , Van Assche Guy , De Clerck Karen
Published: September 2010

Electrospinning is a process to generate a nanofibrous material. Although the working principle of electrospinning is rather straight forward, it is influenced by many parameters. There is still a serious lack of knowledge concerning the influence of the ambient parameters, for which preliminary knowledge reveals that the relative humidity is of primary importance. This article reports the influence of the relative humidity on electrospun polyamide 6 nanofibres. Mixtures of formic acid and acetic acid are used for steady state electrospinning of polyamide 6 nanofibres, for which a steady state table is determined. When the relative humidity increases, the average fiber diameter decreases and the fraction of the less stable γ‐phase crystals in the polyamide diminishes. This effect is explained by absorbed water acting as a plasticizer, reducing the Tg of the polyamide. This article shows the importance of working in climatized conditions during electrospinning to obtain reproducible nanofibres. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
A novel electric elastomer based on starch/transformer oil drop/silicone rubber hybrid
Authors: Hao Limei , Ding Changlin , Zhao Xiaopeng
Published: September 2010

The electrorheological fluid composed of starch particles and silicone oil/transformer oil was dispersed into 107 silicone rubber, and then two types of electric elastomers were prepared in the absence and presence of a curing electric field, respectively. The storage modules were measured using dynamic mechanical analysis with the round disk compression clamp. The results indicate that the storage modulus sensitivity of electric elastomers composed of pure transformer oil is the highest, that of electric elastomers composed of pure silicone oil takes second place, and that of electric elastomers composed of mixture oil is the smallest. For the given starch concentration, the storage modulus sensitivity attains a maximum value of 3.88 when the mass ratio between the transformer oil and 107 silicone rubber is 1. For the given mass ratio of 1, the effects of starch concentration and the presence or absence of the curing electric field on the storage modulus of electric elastomers were studied. When the starch concentration is 5 wt %, the storage modulus of the elastomer without the electric field (denoted as A‐elastomer) is 20.1 kPa, whereas that of the elastomer with the electric field (denoted as B‐elastomer) is 101.8 kPa. The storage modulus sensitivity attains a maximum value of 4.07. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
Cocontinuous phase morphology of asymmetric compositions of polypropylene/high‐density polyethylene blend by the addition of clay
Authors: Dhibar Anup K. , Kim Jin Kon , Khatua Bhanu B.
Published: September 2010

A novel method of developing cocontinuous morphology in 75/25 and 80/20 w/w polypropylene/high density polyethylene (PP/HDPE) blends in the presence of small amount (0.5 phr) of organoclay has been reported. SEM study indicated a reduction in average domain sizes (D) of disperse HDPE when PP, HDPE, and the organoclay were melt‐blended simultaneously at 200°C. However, when the two‐sequential heating protocol was employed, (that is, the organoclay was first intercalated by HDPE chains at 150°C, followed by melt blending of PP at 200°C), very interestingly a cocontinuous morphology was found even for very asymmetric blend compositions. WAXD study revealed the intercalation of both PP and HDPE chains inside the clay galleries, when PP/HDPE and clay were melt‐mixed together at 200°C. However, when the two‐sequential heating protocol was used the organoclay platelets were selectively intercalated by the HDPE chains. Addition of SEPS in the blend decreased the D of HDPE domains in both the blending methods. Thus, the observed cocontinuous morphology in asymmetric composition of PP/HDPE blend in presence of clay is because of the barrier effect of the clay platelets in the HDPE phase that restrict the phase inversion into the domain/matrix morphology. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
Polymerization of ethylene: Some aspects of metallocene catalyst stabilization under homogeneous and heterogeneous reaction conditions
Authors: de Freitas A. J. D. , dos Santos J. H. Z. , Meneghetti S. M. P. , Meneghetti M. R.
Published: September 2010

The development of metallocene‐based catalysts is an important advance on the study of polyolefinic materials. However, due to the rather different conditions that are established in actual applications, only around 3% of these polymers are obtained from metallocene technology. In view of this, novel strategies must be developed to produce metallocene‐based catalysts that are more thermally stable, which is a fundamental requirement to establish metallocene technologies. Homogeneous and heterogeneous polymerizations of ethylene were compared, using the Ph2C(Cp)(Flu)ZrCl2/MAO system. Homogeneous polymerizations were more active than the corresponding supported reactions. At low ethylene pressure, the addition of 1‐hexene increases the activity under homogeneous conditions. Nevertheless, this is not observed on the respective supported systems. At higher pressure conditions, all polymerizations attained higher yields. However, when the reaction temperature increases the activity significantly decreases under homogeneous conditions. Furthermore, when the polymerization was performed under heterogeneous conditions the deactivation was lower. The homogeneous and supported catalytic systems show different characteristics and, in all attempted reactions, immobilization of the molecular catalyst reduces the activity. However, the deactivation ratio was lower when the polymerization was performed under heterogeneous conditions. This means that immobilization of Ph2C(Cp)(Flu)ZrCl2 on silica can improve the thermal stability of the catalytic species. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
Fusion bonding of supercooled poly(ethylene terephthalate) between Tg and Tm
Authors: Li Ruihua , Yao Donggang , Sun Qunhui , Deng Yulin
Published: September 2010

Because of its slowly crystallizing nature, poly(ethylene terephthalate) (PET) can be supercooled into an amorphous glass by rapid quenching. Upon reheating between Tg and Tm, the amorphous PET are subjected to two competing processes: rubber softening and crystallization. Fusion bonding of two such crystallizable amorphous polymer sheets in this processing temperature window is thus a complex process, different from fusion of purely amorphous polymer above Tg or semicrystalline polymer above Tm. In this study, the interfacial morphological development during fusion bonding of supercooled PET in the temperature window between Tg and Tm was studied. A unique double‐zone interfacial morphology was observed at the bond. Transcrystals were found to nucleate at the interface and grow inward toward the bulk and appeared to induce nucleation in the bulk to form a second interfacial region. The size and morphology of the two zones were found to be significantly affected by the fusion bonding conditions, particularly the fusion temperature. The fusion bonding strength determined by the peeling test was found to be significantly affected by the state of crystallization and the morphological development at the bonding interface. Based on the interfacial morphology observed and the bonding strength measured, a fusion bonding mechanism of crystallizable amorphous polymer was proposed. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
The CCL5/CCR5 axis promotes interleukin‐6 production in human synovial fibroblasts
Authors: Tang Chih‐Hsin , Hsu Chin‐Jung , Fong Yi‐Chin
Published: September 2010

Objective

CCL5 (RANTES) was originally identified as a product of activated T cells and plays a crucial role in the inflammatory response. This study was undertaken to investigate the intracellular signaling pathways involved in CCL5‐induced interleukin‐6 (IL‐6) production in human synovial fibroblasts.

Methods

CCL5‐mediated IL‐6 expression was assessed by quantitative polymerase chain reaction and enzyme‐linked immunosorbent assay. The mechanisms of action of CCL5 in different signaling pathways were studied using Western blotting. Knockdown of CCR5 and protein kinase Cδ (PKCδ) protein was achieved by transfection of small interfering RNA (siRNA). Chromatin immunoprecipitation assays were used to study in vivo binding of c‐Jun to the IL‐6 promoter. Transient transfection was used to examine IL‐6 and activator protein 1 (AP‐1) activity.

Results

Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCL5 and CCR5, and expression was higher than that in normal synovial fibroblasts. Stimulation of OASFs with CCL5 induced concentration‐ and time‐dependent increases in IL‐6 production. CCL5‐mediated IL‐6 production was attenuated by CCR5 monoclonal antibody, CCR5 inhibitor (Met‐RANTES), and CCR5 siRNA. Pretreatment with a PKCδ inhibitor (rottlerin), a c‐Src inhibitor (PP2), or an AP‐1 inhibitor (tanshinone IIA) also blocked the potentiating action of CCL5. Treatment of OASFs with CCL5 increased the accumulation of phosphorylated c‐Jun in the nucleus, AP‐1 luciferase activity, and c‐Jun binding to the AP‐1 element on the IL‐6 promoter. CCL5‐mediated AP‐1 luciferase activity and c‐Jun binding to the AP‐1 element were inhibited by Met‐RANTES, rottlerin, and PP2.

Conclusion

The present results suggest that the interaction between CCL5 and CCR5 increases IL‐6 production in human synovial fibroblasts via the PKCδ/c‐Src/c‐Jun and AP‐1 signaling pathways.
Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses
Authors: Stoop Jeroen N. , Harry Rachel A. , von Delwig Alexei , Isaacs John D. , Robinson John H. , Hilkens Catharien M. U.
Published: September 2010

Objective

Tolerogenic dendritic cells (DCs) are antigen‐presenting cells with an immunosuppressive function. They are a promising immunotherapeutic tool for the attenuation of pathogenic T cell responses in autoimmune arthritis. The aims of this study were to determine the therapeutic action of tolerogenic DCs in a type II collagen–induced arthritis model and to investigate their effects on Th17 cells and other T cell subsets in mice with established arthritis.

Methods

Tolerogenic DCs were generated by treating bone marrow–derived DCs with dexamethasone and vitamin D3 during lipopolysaccharide‐induced maturation. Mice with established arthritis received 3 intravenous injections of tolerogenic DCs, mature DCs, or saline. Arthritis severity was monitored for up to 4 weeks after treatment. Fluorescence‐labeled tolerogenic DCs were used for in vivo trafficking studies. The in vivo effect of tolerogenic DCs on splenic T cell populations was determined by intracellular cytokine staining and flow cytometry.

Results

Tolerogenic DCs displayed a semi‐mature phenotype, produced low levels of inflammatory cytokines, and exhibited low T cell stimulatory capacity. Upon intravenous injection into arthritic mice, tolerogenic DCs migrated to the spleen, liver, lung, feet, and draining lymph nodes. Treatment of arthritic mice with type II collagen–pulsed tolerogenic DCs, but not unpulsed tolerogenic DCs or mature DCs, significantly inhibited disease severity and progression. This improvement coincided with a significant decrease in the number of Th17 cells and an increase in the number of interleukin‐10–producing CD4+ T cells, whereas tolerogenic DC treatment had no detectable effect on Th1 cells or interleukin‐17–producing γ/δ T cells.

Conclusion

Treatment with type II collagen–pulsed tolerogenic DCs decreases the proportion of Th17 cells in arthritic mice and simultaneously reduces the severity and progression of arthritis.
Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: Observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts
Authors: Saevarsdottir Saedis , Wedrén Sara , Seddighzadeh Maria , Bengtsson Camilla , Wesley Annmarie , Lindblad Staffan , Askling Johan , Alfredsson Lars , Klareskog Lars
Published: September 2010

Objective

To determine whether cigarette smoking influences the response to treatment in patients with early rheumatoid arthritis (RA).

Methods

We retrieved clinical information about patients entering the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) early RA cohort from 1996 to 2006 (n = 1,998) who were also in the Swedish Rheumatology Register (until 2007). Overall, 1,430 of the 1,621 registered patients were followed up from the time of inclusion in the EIRA cohort. Of these, 873 started methotrexate (MTX) monotherapy at inclusion, and 535 later started treatment with a tumor necrosis factor (TNF) inhibitor as the first biologic agent. The primary outcome was a good response according to the European League Against Rheumatism criteria at the 3‐month visit. The influence of cigarette smoking (current or past) on the response to therapy was evaluated by logistic regression, with never smokers as the referent group.

Results

Compared with never smokers, current smokers were less likely to achieve a good response at 3 months following the start of MTX (27% versus 36%; P = 0.05) and at 3 months following the start of TNF inhibitors (29% versus 43%; P = 0.03). In multivariate analyses in which clinical, serologic, and genetic factors were considered, the inverse associations between current smoking and good response remained (adjusted odds ratio [OR] for MTX response 0.60 [95% CI 0.39–0.94]; adjusted OR for TNF inhibitor response 0.52 [95% CI 0.29–0.96]). The lower likelihood of a good response remained at later followup visits. Evaluating remission or joint counts yielded similar findings. Past smoking did not affect the chance of response to MTX or TNF inhibitors. Evaluating the overall cohort, which reflects all treatments used, current smoking was similarly associated with a lower chance of a good response (adjusted ORs for the 3‐month, 6‐month, 1‐year, and 5‐year visits 0.61, 0.65, 0.78, 0.66, and 0.61, respectively).

Conclusion

Among patients with early RA, current cigarette smokers are less likely to respond to MTX and TNF inhibitors.
Physical activity levels and functional performance in the osteoarthritis initiative: A graded relationship
Authors: Dunlop Dorothy D. , Song Jing , Semanik Pamela A. , Sharma Leena , Chang Rowland W.
Published: September 2010

Objective

Physical activity improves function in adults with arthritis, but it is unknown if there is a graded relationship between physical activity and functional benefit. This study was undertaken to examine the cross‐sectional and longitudinal relationship between self‐reported physical activity and observed functional performance in adults with knee osteoarthritis (OA).

Methods

The Osteoarthritis Initiative cohort included 2,589 patients with knee OA (2,301 with longitudinal followup data) who were ages 45–79 years at baseline. Prospective annual functional performance was assessed for 2 years using timed 20‐meter walk tests. We used linear regression to estimate differences across physical activity quartiles in subsequent function (baseline and 1‐year activity predicts 1‐year and 2‐year function, respectively) adjusted for demographic factors (age, sex, race/ethnicity, education level, and marital status) and health factors (OA severity, knee symptoms, knee pain, knee injury, body mass index, comorbidity, depression, smoking, alcohol use, and other joint pain).

Results

Increasing physical activity levels had a significant graded relationship to functional performance. Adults in physical activity quartile groups from least active to most active had an average gait speed of 4.0, 4.2, 4.3, and 4.5 feet/second, respectively, at baseline (P for trend < 0.001) and 4.0, 4.2, 4.3, and 4.5 feet/second, respectively, after 1 year (P for trend < 0.001); increasing trends remained significant after adjusting for covariates. Findings were similar within sex and age groups.

Conclusion

These prospective data indicate a consistent graded relationship between physical activity level and better performance in adults with knee OA. These findings support guidelines that encourage patients with arthritis who cannot attain minimum recommended physical activity to be as active as possible.
Involvement of PPARα and PPARγ in apoptosis and proliferation of human hepatocarcinoma HepG2 cells
Authors: Maggiora Marina , Oraldi Manuela , Muzio Giuliana , Canuto Rosa Angela
Published: September 2010

Peroxisome proliferator‐activated receptors (PPARs) mediate the effects of various ligands, known as peroxisome proliferators, a heterogeneous class of compounds including industrial chemicals, pharmaceuticals, and biomolecules such as fatty acids and eicosanoids. Among peroxisome proliferators, fibrate derivatives are considered specific ligands for PPARα, whereas eicosanoids, such as PGJ2, for PPARγ. The study aimed to clarify the relation between PPARs and apoptosis or proliferation on the same type of cells, using clofibrate as specific ligand of PPARα and PGJ2 as specific ligand of PPARγ. The cells used were human hepatocarcinoma HepG2 cells. The results showed that PPARα protein content increased in HepG2 cells treated with clofibrate, causing apoptosis in a time‐ and concentration‐dependent way, as evidenced by the citofluorimetric assay and determination of BAD, myc and protein phosphatase 2A protein content. It also emerged that PPARγ increased in the same cells when treated with a specific ligand of this PPAR; in this case the increase of PPARγ did not cause an increase of apoptosis, but a time‐ and concentration‐dependent inhibition of cell proliferation, evidenced by decreased cell numbers and increased number of cells in the G0/G1 phase of the cycle. It may be concluded that PPARα is chiefly related to apoptosis and PPARγ to cell proliferation. Copyright © 2010 John Wiley & Sons, Ltd.
C‐terminal neurofilament phosphorylation fosters neurofilament–neurofilament associations that compete with axonal transport
Authors: Lee Sangmook , Sunil Neethu , Shea Thomas B.
Published: September 2010

Neurofilaments (NFs) associate with each other and with other cytoskeletal elements to form a lattice that supports the mature axon. Phosphorylation contributes to formation of this structure by fostering cation‐dependent interactions among NF sidearms. By inducing NF bundling, phosphorylation impedes their axonal transport. To examine the impact of the known NF kinase cdk5 on these phenomena, transfected cells with constructs expressing GFP‐tagged NF‐H sidearms (lacking the rod domain to preclude assembly) with and without site‐directed mutagenesis of 7 cdk5 consensus sites, and monitored the impact on NF transport and association with the axonal NF bundle. These mutations did not alter transport but pseudo‐phosphorylated mutants displayed a greater association with axonal NF bundles. By contrast, these same mutations in full‐length NF‐H altered NF transport as well as bundling. Since isolated sidearms cannot assemble, they can only interact with NFs via a single sidearm–sidearm interaction, while assembled NFs can form multiple such interactions. These finding suggest that individual sidearm–sidearm interactions are dynamic and do not persist long enough to slow NF transport, and that bundle formation and maintenance depends upon both the long half‐life of NF polymers and the establishment of multiple phosphorylation‐dependent sidearm‐mediated interactions among NFs. © 2010 Wiley‐Liss, Inc.
Target Profiling of a Small Library of Phosphodiesterase 5 (PDE5) Inhibitors using Chemical Proteomics
Authors: Raijmakers Reinout , Dadvar Poupak , Pelletier Sarah , Gouw Joost , Rumpel Klaus , Heck Albert J. R.
Published: September 2010

Inhibitors of phosphodiesterase 5 (PDE5) are widely used for the treatment of erectile dysfunction and pulmonary hypertension. The commercially available inhibitors are effective, well‐tolerated drugs, but differ in their phosphodiesterase specificity. To explore and manipulate the specificity of PDE5 inhibitors, a small library of four inhibitors was synthesized using the structure of known PDE5 inhibitors as a scaffold. Their inhibitory potency towards PDE5 and related family members was evaluated. Next, they were immobilized on a matrix to perform affinity pull‐down assays in rat testis tissue, followed by mass spectrometric (MS) analysis. By using unique peptide spectral counts of identified proteins in the MS analysis, we were able to assess the relative binding of these inhibitors to a large set of proteins, allowing the determination of their selectivity profiles in vitro. For selected proteins of interest, the results were verified using quantitative isotopic dimethyl labeling and immunoblotting, and isothermal titration calorimetry (ITC). For the PDE5 inhibitors, our data reveal that even slight chemical modifications can bias their selectivity significantly towards other interacting proteins, opening up the potential of these compounds to be used as scaffolds for the development of inhibitors for new protein targets. In a broad sense, we demonstrate that the combination of chemical proteomics and unique peptide spectral counting allows for the confident and facile analysis of the differential interactome of bioactive small molecules.
Elevated plasma tissue inhibitor of metalloproteinase‐1 levels predict decreased survival in castration‐resistant prostate cancer patients
Authors: Oh William K. , Vargas Roberto , Jacobus Susanna , Leitzel Kim , Regan Meredith M. , Hamer Peter , Pierce Karen , Brown‐Shimer Sheryl , Carney Walter , Ali Suhail M. , Kantoff Philip W. , Lipton Allan
Published: September 2010

BACKGROUND.

Tissue inhibitor of metalloproteinase‐1 (TIMP‐1) has paradoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of matrix metalloproteinases and apoptosis as well as promotion of angiogenesis and tumor growth. Elevated TIMP‐1 levels have been associated with a poorer prognosis in multiple cancers.

METHODS.

Ethylenediaminetetraacetic acid plasma TIMP‐1 was determined in 362 castration‐resistant prostate cancer (PC) patients using a TIMP‐1 enzyme‐linked immunosorbent assay. All patients with castration‐resistant PC and available plasma were identified from an institutional database. Overall survival was analyzed using the Kaplan‐Meier method and Cox modeling on plasma TIMP‐1 tertiles.

RESULTS.

Patients were evaluated in pilot (n = 60) and primary (n = 302) sets. Median follow‐up from diagnosis was 5.8 and 6.6 years, respectively. Median plasma TIMP‐1 levels were 335 and 183 ng/mL in the pilot and primary sets, respectively. Overall survival was significantly shorter with each higher tertile of TIMP‐1 in both datasets (P<.001). For the primary cohort, hazard ratio of (HR) death and median survival by plasma TIMP‐1 tertile levels were: low, HR 1.0, 43 months; middle, HR 1.7, 27 months; high, HR 2.4, 19 months. In the primary set, significant covariates in the adjusted Cox regression model were: TIMP‐1 level (mid or high vs low tertile), prostate‐specific antigen (>20 vs ≤20 ng/mL), alkaline phosphatase (>102 vs ≤102 U/L), Eastern Cooperative Oncology Group performance status (1 + vs 0), and Gleason score (7 or 8 vs ≤6).

CONCLUSIONS.

Elevated plasma TIMP‐1 levels predicted decreased survival in metastatic castration‐resistant PC patients, independent of known prognostic markers. Cancer 2011. © 2010 American Cancer Society.
Therapeutic role of lymphadenectomy for cervical cancer
Authors: Shah Monjri , Lewin Sharyn N. , Deutsch Israel , Burke William M. , Sun Xuming , Herzog Thomas J. , Wright Jason D.
Published: September 2010

BACKGROUND.

Despite the diagnostic value of lymphadenectomy for early‐stage cervical cancer, its therapeutic role is unknown. We examined the therapeutic potential of extensive lymphadenectomy in women with early‐stage cervical cancer.

METHODS.

Women with stage IA2‐IIA cervical cancer who underwent radical hysterectomy with lymphadenectomy in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Patients were stratified according to the number of nodes removed. The effect of the extent of lymphadenectomy on overall and cancer‐specific survival was examined using multivariable Cox proportional hazards models. Separate analyses were performed for node positive and node negative patients.

RESULTS.

Among 5522 women, 893 (16%) had <10 nodes, 2030 (37%) had 11‐20, 1487 (27%) had 21‐30 nodes, and 1112 (20%) had >30 nodes removed. Black women, those >65 years of age and those diagnosed later in the study, were less likely to have 10 or more nodes removed (P < .05 for all). Among women with positive lymph nodes, a more extensive lymphadenectomy had no effect on survival (HR = 0.75; 95% CI, 0.47‐1.22). For women with negative lymph nodes, a more extensive lymphadenectomy was associated with improved survival. Compared with node negative patients with less than 10 nodes removed, patients with 21‐30 nodes removed were 24% (HR = 0.76; 95% CI, 0.53‐1.09) less likely to die, whereas those with >30 nodes removed were 37% (HR = 0.64; 95% CI, 0.43‐0.96) less likely to die from their tumors.

CONCLUSIONS.

Node negative, early‐stage cervical cancer patients who undergo a more extensive lymphadenectomy have an improved survival. Cancer 2011. © 2010 American Cancer Society.
The signal of suicide rates seen from a distance in patients with pancreatic cancer
Authors: Greenberg Donna B.
Published: September 2010

Although suicide is rare in patients with pancreatic cancer, the higher rate of suicide signals that the anguish of clinical depression is common. Older men, more alone, with a history of substance abuse and depression, soon after diagnosis, are more at risk for suicide; attention to psychiatric syndromes is an integral part of cancer care.
Cancer: More of polygenic disease and less of multiple mutations? A quantitative viewpoint
Authors: Bredberg Anders
Published: September 2010

The focus of cancer research is on cancer‐specific mutations, with most clinical trials involving targeted drugs. Huge numbers of DNA lesions and tumor resistance events, in each of the >1013 cells of a human individual, form a striking contrast to the low, and also very narrow, cancer incidence window (10−1‐100). A detailed consideration of these quantitative observations seems to question the present paradigm, while suggesting that a systemic regulatory network mechanism is a stronger determinant for overt cancer disease, as compared with cancer‐specific gene products. If we shall ever achieve major improvements in survival, we must gain understanding of this systemic network, rather than targeting therapy to a limited set of molecules or mutations. This may give us new opportunities for development of highly potent therapeutic tools. Cancer 2011. © 2010 American Cancer Society.
Promoter methylation of the RGC32 gene in nonsmall cell lung cancer
Authors: Kim Dong Sun , Lee Ji Yun , Lee Su Man , Choi Jin Eun , Cho Sukki , Park Jae Yong
Published: September 2010

BACKGROUND:

Lung cancer is the leading cause of cancer‐related deaths worldwide. Epigenetic inactivation of certain genes by aberrant promoter methylation is recognized as a crucial component in the initiation and progression of lung cancer. Response gene to complement 32 (RGC32) has been identified as a cell cycle regulator induced by activation of complements; however, its role in carcinogenesis is still controversial.

METHODS:

The authors examined the methylation status in the promoter region of RGC32 gene in nonsmall cell lung cancers (NSCLCs) using a methylation‐specific PCR and correlated the results with clinicopathological features.

RESULTS:

RGC32 methylation was found in 45 of 173 NSCLCs (26.0%) and was related to the gene expression. RGC32 methylation was more frequent in females than in males (P<0.05). RGC32 methylation was not significantly associated with the prognosis of patients; however, when the patients were categorized by TP53 mutational status, the effect of RGC32 methylation on prognosis was significantly different between those with and without TP53 mutations (P = .005 [test for homogeneity]). Specifically, RGC32 methylation was associated with significantly worse survival in the cases with wild‐type TP53, whereas it exhibited a better survival outcome in the cases with TP53 mutations.

CONCLUSIONS:

The current findings suggest that methylation‐associated down‐regulation of RGC32 plays an important role in the pathogenesis of NSCLC, particularly in females. However, further studies with a large number of cases are needed to confirm the authors' findings. Cancer 2011. © 2010 American Cancer Society.
Advanced stage mucinous adenocarcinoma of the ovary is both rare and highly lethal
Authors: Zaino Richard J. , Brady Mark F. , Lele Subodh M. , Michael Helen , Greer Benjamin , Bookman Michael A.
Published: September 2010

BACKGROUND:

Primary mucinous adenocarcinomas of the ovary are uncommon, and their biological behavior is uncertain. Retrospective studies have suggested that many mucinous carcinomas initially diagnosed as primary to the ovary have in fact metastasized from another site. A prospective randomized trial provided an opportunity to estimate the frequency of mucinous tumors, diagnostic reproducibility, and clinical outcomes.

METHODS:

A phase 3 trial enrolled 4000 women with stage III or IV ovarian carcinoma, treated by surgical staging and debulking, with randomization to one of five chemotherapeutic arms. Slides and pathology reports classified as primary mucinous carcinoma were reviewed independently by three pathologists. Cases were reclassified as primary or metastatic to the ovary according to two methods. Overall survival (OS) of reclassified groups was compared within the groups and with that of patients with serous carcinomas.

RESULTS:

Forty‐four cases were classified as mucinous adenocarcinoma upon review. Using either method, only about one third were interpreted by the three reviewers as primary mucinous carcinomas. Reproducibility of interpretations among the reviewers was high, with unanimity of opinion in 30 (68%) cases. The median survival (MS) did not differ significantly between the groups interpreted as primary or metastatic, but the OS was significantly less than that for women with serous carcinoma (14 vs 42 months, P < 0.001).

CONCLUSION:

Advanced stage mucinous carcinoma of the ovary is very rare and is associated with poor OS. Many mucinous adenocarcinomas that are diagnosed as primary ovarian neoplasms appear to be metastatic to the ovary. Cancer 2011. © 2010 American Cancer Society.
Targeted use of fluorescence in situ hybridization (FISH) in cytospin preparations
Authors: da Cunha Santos Gilda , Ko Hyang Mi , Geddie William R. , Boerner Scott L. , Lai Shui Wun , Have Cherry , Kamel‐Reid Suzanne , Bailey Denis
Published: September 2010

BACKGROUND:

Fluorescence in situ hybridization (FISH) results from fine needle aspirates (FNA) of B‐cell non‐Hodgkin lymphomas (NHLs) were reviewed to 1) investigate the value added by using specific gene rearrangement probes to lymphoma diagnosis, prognosis, and subtyping; and 2) evaluate the prevalence of cytogenetic alterations other than specific translocations.

METHODS:

FISH results from assays performed on cytospin preparations from NHL FNAs over a 6‐year period (2003‐2009) were selected. Immunophenotyping, clinical data, and cytomorphologic data were reviewed according to the current World Health Organization (WHO) classification system. Hybridized probes, the purpose for the assay (subtyping or prognosis), and the cytogenetic abnormalities observed were retrieved from cytology reports. Data was categorized according to specific rearrangements and other chromosomal abnormalities.

RESULTS:

Successful results were obtained in 284 (95.3%) of 298 cases from 282 patients. Abnormalities were found in 216 (76%) cases and 68 (24%) did not show alteration. Among cases submitted for subtyping, 198 showed FISH‐positive results, and specific gene rearrangements were found in 122 (61.6%) cases as follows: follicular 82, mantle cell 21, marginal zone 3, “dual hit” 13, and Burkitt lymphoma 3. In 21 cases, abnormalities were useful for prognosis. Nonspecific alterations alone or in combination with translocations were found in 98 cases.

CONCLUSIONS:

FISH performed on cytospin preparations was useful for confirmation of specific subclasses of NHL and may also provide valuable prognostic information. Cytogenetic abnormalities other than specific translocations were frequently found and could provide supportive evidence for a definitive diagnosis of lymphoma in FNA. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.
Should adequacy criteria in cervicovaginal cytology be modified after radiotherapy, chemotherapy, or hysterectomy?
Authors: Lu Chien‐Hsing , Chang Chia‐Che , Ho Esther Shih‐Chu , Chen Su‐Ju , Lin Shu‐Jiuan , Fu Tsai‐Feng , Chang Ming‐Chen
Published: September 2010

BACKGROUND.

The general criterion of an unsatisfactory Papanicolaou (Pap) test in the 2001 version of the Bethesda system is not applicable to patients after treatment with radiotherapy, chemotherapy, or hysterectomy. The current study was performed to determine whether specimen adequacy criteria for Pap tests should be modified for these conditions.

METHODS.

Consecutive patients who underwent conventional Pap tests between March and August 2006 were reviewed. The original reports were done according to the 2001 Bethesda system, with cellularity criteria modified in patients with a history of radiotherapy, chemotherapy, or hysterectomy. The slides of these patients were reviewed again. The degrees of cellularity, obscuring red blood cells, and inflammation were recorded.

RESULTS.

The final analyses included 7033 patients for which there were complete data. The original interpretation was unsatisfactory in 4.4% of all samples. When the 1337 slides obtained from patients with a history of radiotherapy, chemotherapy, and/or hysterectomy were reviewed using the general satisfactory threshold of >8000 squamous cells/slide and <75% of the epithelium obscured, the incidence of unsatisfactory Pap tests increased from 4.3% to 13.2% (176 of 1337 slides). The odds ratios for unsatisfactory Pap tests for a history of radiotherapy, chemotherapy, and age >50 years were 2.70, 2.51, and 1.39, respectively. The majority of unsatisfactory Pap tests were because of low cellularity. The lower limits of adequate cellularity after radiotherapy or chemotherapy can be set at 2000 cells/slide, which can lower the unsatisfactory rate while at the same time resulting in no increase in the false‐negative rate. Hysterectomy alone was not found to be associated with unsatisfactory Pap tests.

CONCLUSIONS.

In patients who received pelvic radiotherapy or chemotherapy, the incidence of low‐cellularity Pap tests was unacceptably high. A lower cellularity (estimated 2000 cell/slide) could be used as a satisfactory threshold. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.
Maternal touch and feed as critical regulators of behavioral and stress responses in the offspring
Authors: Walker Claire‐Dominique
Published: September 2010

For half a century, Seymour Levine's pioneering work on the interactions between mother and infant have helped us understand the critical early factors that shape physiology and behavior in the adult offspring. The work from my laboratory described in this review was based on many experiments by Levine and coworkers demonstrating that the quantity and quality of maternal milk and of maternal‐infant contact influence different aspects of the hypothalamus‐pituitary‐adrenal (HPA) activity in the neonate. We have extended this work by showing that maternal high‐fat feeding during the prenatal and lactational period blunts stress responsiveness in neonatal pups, in part mediated by increased circulating leptin levels in the offspring. The blunting of stress responses during this specific neonatal period might be beneficial to prevent the negative effects of exaggerated glucocorticoid secretion on the developing brain. In line with Levine's previous work, we found that maternal licking of the pups reduced stress responsiveness and inflammation in pups subjected to modest repeated pain during the first weeks of life and that it also blunted adult sensitivity to thermal pain. These studies have important implications for human infants as mechanisms aimed at reducing stress responsiveness can be considered protective to the developing brain from exaggerated and untimely neuroendocrine and sympathetic stimulation. Non‐invasive interventions targeted at maternal nutrition and maternal care are relatively easy to implement and might have a significant effect on the health outcome of the offspring, particularly in a vulnerable population of term and pre‐term babies. © 2010 Wiley Periodicals, Inc. Dev Psychobiol 52: 638–650, 2010.
Smn deficiency causes neuritogenesis and neurogenesis defects in the retinal neurons of a mouse model of spinal muscular atrophy
Authors: Liu Hong , Beauvais Ariane , Baker Adam N. , Tsilfidis Catherine , Kothary Rashmi
Published: September 2010

The eye is an excellent model for the study of neuronal development and pathogenesis of central nervous system disorders because of its relative ease of accessibility and the well‐characterized cellular makeup. We have used this model to study spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival of motor neuron 1 gene (SMN1). We have investigated the expression pattern of mouse Smn mRNA and protein in the neural retina and the optic nerve of wild type mice. Smn protein is present in retinal ganglion cells and amacrine cells within the neural retina as well as in glial cells in the optic nerve. Histopathological analysis in phenotype stage SMA mice revealed that Smn deficiency is associated with a reduction in ganglion cell axon and glial cell number in the optic nerve, as well as compromised cellular processes and altered organization of neurofilaments in the neural retina. Whole mount preparation and retinal neuron primary culture provided further evidence of abnormal synaptogenesis and neurofilament accumulation in the neurites of Smn‐deficient retinal neurons. A subset of amacrine cells is absent, in a cell‐autonomous fashion, in the retina of SMA mice. Finally, the retinas of SMA mice have altered electroretinograms. Altogether, our study has demonstrated defects in axodendritic outgrowth and cellular composition in Smn‐depleted retinal neurons, indicating a role for Smn in neuritogenesis and neurogenesis, and providing us with an insight into pathogenesis of SMA. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 71: 153‐169, 2011
Granulocyte‐colony stimulating factor drives the in vitro differentiation of human dendritic cells that induce anergy in naïve T cells
Authors: Rossetti Maura , Gregori Silvia , Roncarolo Maria Grazia
Published: September 2010

G‐CSF is a modulator of T‐cell and DC functions. Previous reports show that monocytes from G‐CSF‐treated (post‐G) healthy donors differentiate into tolerogenic DC in vitro in the presence of autologous serum, containing high levels of IL‐10 and IFN‐α, and in turn induce type 1 Treg (Tr1) cells. However, the direct effect of G‐CSF on DC differentiation was not investigated. Here, we show that monocytes differentiated in the presence of exogenous G‐CSF (G‐DC) remain CD14+CD1a−, but acquire a DC‐like morphology, express CD83 and CD86 and low levels of the tolerogenic markers Ig‐like transcript (ILT)4 and HLA‐G. G‐DC spontaneously produce IL‐10 and, upon stimulation, low levels of IL‐12. G‐DC display low stimulatory capacity and induce anergy in naïve T cells, but do not confer suppressive function. Therefore, in vitro differentiation of monocyte‐derived DC in the presence of G‐CSF can replicate some but not all features of post‐G DC. These findings indicate that the tolerogenic properties of G‐CSF do not exclusively reside in its direct effect on DC, which in turn induce T‐cell anergy, but also in its ability to generate a tolerogenic milieu in vivo, which is necessary for Tr1 cell induction and cannot be replicated in vitro.