bluuebunny/crossref_metadata_2025 huggingface dataset:
Consensus Recommendations for the Use of Anti-EGFR Therapies in Metastatic Colorectal Cancer
Authors: Cripps C. , Gill Sharlene , Ahmed S. , Colwell B. , Dowden S. , Kennecke H. , Maroun J. , Samson B. , Thirlwell M. , Wong R.
Published: January 2011

In January 2010, a panel of Canadian oncologists with particular expertise in colorectal cancer (CRC) gathered to develop a consensus guideline on the use of therapies against the epidermal growth factor receptor (EGFR) in the management of metastatic CRC (MCRC). This paper uses a case-based approach to summarize the consensus recommendations developed during that meeting. These are the consensus recommendations: 1. Testing for the KRAS status of the tumour should be performed as soon as an EGFR inhibitor is being considered as an option for treatment. 2. Anti-EGFR therapies are not recommended for the treatment of patients with tumours showing mutated KRAS status. 3. For a patient with wild-type KRAS and an Eastern Cooperative Oncology Group status of 0–2, whose mCRC has previously been treated with a fluoropyrimidine, irinotecan, and oxaliplatin, switching to an EGFR inhibitor is a recommended strategy. 4. Cetuximab, cetuximab plus irinotecan, and panitumumab are all options for third-line therapy in patients with wild-type KRAS, provided that tolerability is acceptable.
The Src-Like Adaptor Protein Regulates GM-CSFR Signaling and Monocytic Dendritic Cell Maturation
Authors: Liontos Larissa M. , Dissanayake Dilan , Ohashi Pamela S. , Weiss Arthur , Dragone Leonard L. , McGlade C. Jane
Published: January 2011

GM-CSF is an important cytokine involved in myeloid differentiation and inflammatory processes. Signaling through the GM-CSFR also plays a critical role in the generation of monocyte-derived dendritic cells (DC). In this article, we report that the Src-like adaptor protein (SLAP) functions as a negative regulator of the GM-CSFR. In bone marrow-derived DC (BM-DC) lacking SLAP and the closely related SLAP2, downregulation of GM-CSFRβ is impaired, leading to enhanced phosphorylation of Jak2 and prolonged activation of Akt and Erk1/2 in response to GM-CSF stimulation. Compared with wild-type bone marrow, SLAP/SLAP2−/− bone marrow gave rise to similar numbers of CD11c+ and CD11b+ DC, but SLAP/SLAP2−/− BM-DC failed to acquire high levels of MHC class II, CD80, and CD86, indicating an impairment in maturation. Furthermore, MHC class II expression in SLAP/SLAP2−/− BM-DC was rescued by decreasing GM-CSF concentration, suggesting that enhanced GM-CSF signaling mediates the block in maturation. In addition, SLAP/SLAP2−/− BM-DC produced less IL-12 and TNF-α in response to LPS compared with controls and failed to stimulate T cells in an MLR. Ag-specific T cell activation assays showed that SLAP/SLAP2−/− BM-DC were less robust at inducing IFN-γ secretion by DO11.10 T cells. These results indicated that SLAP-mediated GM-CSFR regulation is important for the generation of functionally mature monocytic DC.
Tribbles 3: A Novel Regulator of TLR2-Mediated Signaling in Response to Helicobacter pylori Lipopolysaccharide
Authors: Smith Sinéad M. , Moran Anthony P. , Duggan Shane P. , Ahmed Salah E. , Mohamed Abdelhafeez S. , Windle Henry J. , O’Neill Luke A. , Kelleher Dermot P.
Published: January 2011

Helicobacter pylori causes chronic gastritis, peptic ulcers, and gastric carcinoma. Gastric epithelial cells provide the first point of contact between H. pylori and the host. TLRs present on these cells recognize various microbial products, resulting in the initiation of innate immunity. Although previous reports investigated TLR signaling in response to intact H. pylori, the specific contribution of H. pylori LPS with regard to functional genomics and cell-signaling events has not been defined. This study set out to define downstream signaling components and altered gene expression triggered by H. pylori LPS and to investigate the role of the signaling protein tribbles 3 (TRIB3) during the TLR-mediated response to H. pylori LPS. Cotransfections using small interfering RNA and dominant-negative constructs demonstrated that H. pylori LPS functions as a classic TLR2 ligand by signaling through pathways involving the key TLR signaling components MyD88 adaptor-like, MyD88, IRAK1, IRAK4, TNFR-associated factor 6, IκB kinase β, and IκBα. Microarray analysis, real-time PCR, and ELISA revealed the induction of a discrete pattern of chemokines as a direct effect of LPS:TLR2 signaling. H. pylori infection was associated with decreased expression of TRIB3 in human gastric epithelial cell lines and tissue samples. Additionally, H. pylori decreased expression of C/EBP homologous protein and activating transcription factor 4, the transcription factors involved in the induction of TRIB3 expression. Furthermore, knockdown of TRIB3 and C/EBP homologous protein enhanced TLR2-mediated NF-κB activation and chemokine induction in response to H. pylori LPS. Thus, modulation of TRIB3 by H. pylori and/or its products may be an important mechanism during H. pylori-associated pathogenesis.
IL-33 and M2a Alveolar Macrophages Promote Lung Defense against the Atypical Fungal Pathogen Pneumocystis murina
Authors: Nelson Michael P. , Christmann Benjamin S. , Werner Jessica L. , Metz Allison E. , Trevor Jennifer L. , Lowell Clifford A. , Steele Chad
Published: January 2011

We have recently reported that mice deficient in the myeloid Src-family tyrosine kinases Hck, Fgr, and Lyn (Src triple knockout [TKO]) had augmented innate lung clearance of Pneumocystis murina that correlated with a higher ability of alveolar macrophages (AMs) from these mice to kill P. murina. In this article, we show that despite possessing enhanced killing, AMs from naive Src TKO mice did not demonstrate enhanced inflammatory responses to P. murina. We subsequently discovered that both AMs and lungs from P. murina-infected Src TKO mice expressed significantly greater levels of the M2a markers RELM-α and Arg1, and the M2a-associated chemokines CCL17 and CCL22 than did wild-type mice. IL-4 and IL-13, the primary cytokines that promote M2a polarization, were not differentially produced in the lungs between wild-type and Src TKO mice. P. murina infection in Src TKO mice resulted in enhanced lung production of the novel IL-1 family cytokine IL-33. Immunohistochemical analysis of IL-33 in lung tissue revealed localization predominantly in the nucleus of alveolar epithelial cells. We further demonstrate that experimental polarization of naive AMs to M2a resulted in more efficient killing of P. murina compared with untreated AMs, which was further enhanced by the addition of IL-33. Administration of IL-33 to C57BL/6 mice increased lung RELM-α and CCL17 levels, and enhanced clearance of P. murina, despite having no effect on the cellular composition of the lungs. Collectively, these results indicate that M2a AMs are potent effector cells against P. murina. Furthermore, enhancing M2a polarization may be an adjunctive therapy for the treatment of Pneumocystis.
Response of Thermocouples Interfaced to Electrothermometers When Immersed in 5 Water Bath Temperatures
Authors: Long Blaine C. , Jutte Lisa S. , Knight Kenneth L.
Published: January 2011

Context:

Thermocouples and electrothermometers are used in therapeutic modality research. Until recently, researchers assumed that these instruments were valid and reliable.

Objective:

To examine 3 different thermocouple types in 5°C, 15°C, 18.4°C, 25°C, and 35°C water baths.

Design:

Randomized controlled trial.

Setting:

Therapeutic modality laboratory.

Intervention(s):

Eighteen thermocouple leads were inserted through the wall of a foamed polystyrene cooler. The cooler was filled with water. Six thermocouples (2 of each model) were plugged into the 6 channels of the Datalogger and 6 randomly selected channels in the 2 Iso-Thermexes. A mercury thermometer was immersed into the water and was read every 10 seconds for 4 minutes during each of 6 trials. The entire process was repeated for each of 5 water bath temperatures (5°C, 15°C, 18.4°C, 25°C, 35°C).

Main Outcome Measure(s):

Temperature and absolute temperature differences among 3 thermocouple types (IT-21, IT-18, PT-6) and 3 electrothermometers (Datalogger, Iso-Thermex calibrated from −50°C to 50°C, Iso-Thermex calibrated from −20°C to 80°C).

Results:

Validity and reliability were dependent on thermocouple type, electrothermometer, and water bath temperature (P < .001; modified Levene P < .05). Statistically, the IT-18 and PT-6 thermocouples were not reliable in each electrothermometer; however, these differences were not practically different from each other. The PT-6 thermocouples were more valid than the IT-18s, and both thermocouple types were more valid than the IT-21s, regardless of water bath temperature (P < .001).

Conclusions:

The validity and reliability of thermocouples interfaced to an electrothermometer under experimental conditions should be tested before data collection. We also recommend that investigators report the validity, the reliability, and the calculated uncertainty (validity + reliability) of their temperature measurements for therapeutic modalities research. With this information, investigators and clinicians will be better able to interpret and compare results and conclusions.
Sweat Rates, Sweat Sodium Concentrations, and Sodium Losses in 3 Groups of Professional Football Players
Authors: Godek Sandra Fowkes , Peduzzi Chris , Burkholder Richard , Condon Steve , Dorshimer Gary , Bartolozzi Arthur R.
Published: January 2011

Context:

Sweat sodium losses have never been reported in a large cohort of American football players.

Objective:

To compare sweat rates (SwtRs), sweat sodium concentrations (SwtNa+), and sodium losses in 3 groups of players (backs and receivers [BK], linebackers and quarterbacks [LB/QB], and linemen [LM]) to determine if positional differences and, therefore, size differences exist.

Design:

Observational study.

Setting:

Data were collected during practices in the second week of 2 consecutive training camps. The wet bulb globe temperature was 78.5°F ± 3.5°F (25.9°C ± 1.9°C).

Patients or Other Participants:

Eighteen BK, 12 LB/QB, and 14 LM volunteered.

Intervention(s):

Sterile sweat patches were applied to the right forearm after the skin was appropriately cleaned. The patches were removed during practice, placed in sterile tubes, centrifuged, frozen, and later analyzed by flame photometry.

Main Outcome Measure(s):

Sweat rate, SwtNa+, and sodium loss. We calculated SwtR by change in mass adjusted for urine produced and fluids consumed divided by practice time in hours.

Results:

Other than age, physical characteristics were different among groups (P < .001). The SwtR was different among groups (F2,41  =  7.3, P  =  .002). It was lower in BK (1.42 ± 0.45 L/h) than in LB/QB (1.98 ± 0.49 L/h) (P < .05) and LM (2.16 ± 0.75 L/h) (P < .01), but we found no differences between SwtRs for LB/QB and LM. The SwtNa+ was not different among groups (BK  =  50 ± 16 mEq/L, LB/QB  =  48.2 ± 23 mEq/L, and LM  =  52.8 ± 25 mEq/L) and ranged from 15 to 99 mEq/L. Sweat sodium losses ranged from 642 mg/h to 6.7 g/h, and findings for group comparisons approached significance (P  =  .06). On days when players practiced 4.5 hours, calculated sodium losses ranged from 2.3 to 30 g/d.

Conclusions:

The BK sweated at lower rates than did the midsized LB/QB and large LM, but LB/QB sweated similarly to LM. Sweat sodium concentration and daily sodium losses ranged considerably. Heavy, salty sweaters require increased dietary consumption of sodium during preseason.
A cross-sectional evaluation of computer literacy among medical students at a tertiary care teaching hospital in Mumbai (Bombay)
Authors: Panchabhai TS , Dangayach NS , Mehta VS , Patankar CV , Rege NN
Published: January 2011

Background:

Computer usage capabilities of medical students for introduction of computer-aided learning have not been adequately assessed.

Aim:

Cross-sectional study to evaluate computer literacy among medical students.

Settings and Design:

Tertiary care teaching hospital in Mumbai, India.

Materials and Methods:

Participants were administered a 52-question questionnaire, designed to study their background, computer resources, computer usage, activities enhancing computer skills, and attitudes toward computer-aided learning (CAL). The data was classified on the basis of sex, native place, and year of medical school, and the computer resources were compared. The computer usage and attitudes toward computer-based learning were assessed on a five-point Likert scale, to calculate Computer usage score (CUS - maximum 55, minimum 11) and Attitude score (AS - maximum 60, minimum 12). The quartile distribution among the groups with respect to the CUS and AS was compared by chi-squared tests. The correlation between CUS and AS was then tested.

Results:

Eight hundred and seventy-five students agreed to participate in the study and 832 completed the questionnaire. One hundred and twenty eight questionnaires were excluded and 704 were analyzed. Outstation students had significantly lesser computer resources as compared to local students (P<0.0001). The mean CUS for local students (27.0±9.2, Mean±SD) was significantly higher than outstation students (23.2±9.05). No such difference was observed for the AS. The means of CUS and AS did not differ between males and females. The CUS and AS had positive, but weak correlations for all subgroups.

Conclusion:

The weak correlation between AS and CUS for all students could be explained by the lack of computer resources or inadequate training to use computers for learning. Providing additional resources would benefit the subset of outstation students with lesser computer resources. This weak correlation between the attitudes and practices of all students needs to be investigated. We believe that this gap can be bridged with a structured computer learning program.
Global analysis of cloud field coverage and radiative properties, using morphological methods and MODIS observations
Authors: Bar-Or R. Z. , Altaratz O. , Koren I.
Published: January 2011

Abstract. The recently recognized continuous transition zone between detectable clouds and cloud-free atmosphere ("the twilight zone") is affected by undetectable clouds and humidified aerosol. In this study, we suggest to distinguish cloud fields (including the detectable clouds and the surrounding twilight zone) from cloud-free areas, which are not affected by clouds. For this classification, a robust and simple-to-implement cloud field masking algorithm which uses only the spatial distribution of clouds, is presented in detail. A global analysis, estimating Earth's cloud field coverage (50° S–50° N) for 28 July 2008, using the Moderate Resolution Imaging Spectroradiometer (MODIS) data, finds that while the declared cloud fraction is 51%, the global cloud field coverage reaches 88%. The results reveal the low likelihood for finding a cloud-free pixel and suggest that this likelihood may decrease as the pixel size becomes larger. A global latitudinal analysis of cloud fields finds that unlike oceans, which are more uniformly covered by cloud fields, land areas located under the subsidence zones of the Hadley cell (the desert belts), contain proper areas for investigating cloud-free atmosphere as there is 40–80% probability to detect clear sky over them. Usually these golden-pixels, with higher likelihood to be free of clouds, are over deserts. Independent global statistical analysis, using MODIS aerosol and cloud products, reveals a sharp exponential decay of the global mean aerosol optical depth (AOD) as a function of the distance from the nearest detectable cloud, both above ocean and land. Similar statistical analysis finds an exponential growth of mean aerosol fine-mode fraction (FMF) over oceans when the distance from the nearest cloud increases. A 30 km scale break clearly appears in several analyses here, suggesting this is a typical natural scale of cloud fields. This work shows different microphysical and optical properties of cloud fields, urging to separately investigate cloud fields and cloud-free atmosphere in future climate research.
Ancient versus modern mineral dust transported to high-altitude alpine glaciers evidences saharan sources and atmospheric circulation changes
Authors: Thevenon F. , Chiaradia M. , Adatte T. , Hueglin C. , Poté J.
Published: January 2011

Abstract. Mineral dust aerosols collected during the years 2008/09 at the high-altitude research station Jungfraujoch (46°33' N, 7°59' E; 3580 m a.s.l.) were compared to windblown mineral dust deposited at the Colle Gnifetti glacier (45°55' N, 7°52' E, 4455 m a.s.l.) over the last millennium. Insoluble dust has been characterized in terms of mineralogy, Sr and Nd isotopic ratios, and trace element composition. Results demonstrate that the Saharan origin of the airborne dust did not change significantly throughout the past. Backward trajectories analysis of modern analogs furthermore confirms that major dust sources are situated in the north-central to north-western part of the Saharan desert. By contrast, less radiogenic Sr isotopic compositions are associated with lower abundances of crustal elements during low rates of dust deposition, suggesting intercontinental transport of background dust rather than activation of a secondary source. Saharan dust mobilization and meridional advection of air masses were relatively reduced during the second part of the Little Ice Age (ca. 1690–1870), except within the greatest Saharan dust event deposited around 1780–1790. Higher dust deposition with larger mean grain size and Saharan fingerprint began ca. 20 years after the industrial revolution of 1850, suggesting that increased mineral dust transport over the Alps during the last century was primarily due to drier winters in North Africa and stronger spring/summer North Atlantic southwesterlies, rather than to direct anthropogenic sources. Meanwhile, increasing carbonaceous particle emissions from fossil fuels combustion combined to higher lead enrichment factor during the last century, point to concomitant anthropogenic sources of particulate pollutants reaching high-altitude European glaciers.
Manganese redox cycling in Lake Imandra: impact on nitrogen and the trace metal sediment record
Authors: Ingri J. , Pekka L. , Dauvalter V. , Rodushkin I. , Peinerud E.
Published: January 2011

Abstract. Sediment and water samples from the mine-polluted Yokostrovskaya basin in Lake Imandra have been analysed. Three major processes have influenced the accumulation and distribution of metals in the sediment: (1) Development of the apatite-nepheline and the sulfide ore mining industries. (2) Secondary formation of sulphides in the upper sediment column. (3) Redox cycling of Mn in the surface sediment and in the bottom water. This study demonstrate the dominant role of the Mn redox cycling in controlling distribution of several major and trace elements, especially during the winter stratification period. Mn oxides act as a major scavenger and carrier for the non-detrital fraction of Al, Ca, K, Mg, P, Ba, Co, Cu, Ni, Mo and Zn in the bottom water. Aluminium, Ca, K, Mg, P, Cu, Ni and Zn are mainly sorbed at the surface of the particulate Mn phase, while Ba and Mo form a phase (or inner sphere complex) with Mn. Co is associated with the Mn-rich phase, probably by oxidation of Co(II) to a trivalent state by the particulate Mn surface. Formation and dissolution of Mn particles most likely also control anoxic ammonium oxidation to nitrate and reduction of nitrate to N2. It is shown that secondary sulphides in Lake Imandra sediments are fed with trace metals primarily scavenged from the dissolved phase in the water column. This enrichment process, driven by the Mn-redox cycle, therefore changes the sediment record by the transfer of a dissolved pollution signal to the particulate sediment record, thus making it more complicated to trace direct influence of particles from different pollution sources.
Association of foot symptoms with self‐reported and performance‐based measures of physical function: The Johnston County osteoarthritis project
Authors: Golightly Yvonne M. , Hannan Marian T. , Shi Xiaoyan Amy , Helmick Charles G. , Renner Jordan B. , Jordan Joanne M.
Published: January 2011

Objective

To examine associations of foot symptoms with self‐reported and performance‐based measures of physical function in a large, biracial, community‐based sample of individuals ages ≥45 years.

Methods

Data from 2,589 Johnston County participants (evaluated in 1999–2004) were used in cross‐sectional analyses. The presence of foot symptoms was defined as pain, aching, or stiffness of at least one foot on most days. Physical function was assessed by the total Stanford Health Assessment Questionnaire (HAQ) score (0, >0 but <1, and ≥1), timed 5 repeated chair stands (completion time <12 seconds, ≥12 seconds, and unable), and 8‐foot walk time (<3.35 seconds and ≥3.35 seconds). Separate multivariable logistic regression models examined associations between foot symptoms and physical function measures, controlling for age, race, sex, body mass index, radiographic knee osteoarthritis, radiographic hip osteoarthritis, knee symptoms, hip symptoms, and depressive symptoms. Interaction terms between each of the 3 physical function measures and each demographic and clinical characteristic were examined.

Results

The prevalence of foot symptoms was 37%. Participants with foot symptoms were more likely than those without symptoms to have higher HAQ scores (adjusted odds ratio [OR] 1.79, 95% confidence interval [95% CI] 1.50–2.12). Among obese participants, those with foot symptoms had longer chair stand (adjusted OR 1.38, 95% CI 1.04–1.87) and 8‐foot walk times (adjusted OR 1.61, 95% CI 1.21–2.15) than those without symptoms.

Conclusion

Foot symptoms were independently and significantly associated with 2 of 3 measures of poorer physical function. Interventions for foot symptoms may be important for helping patients prevent or deal with an existing decline in physical function.
An efficient one‐pot synthesis of 2‐benzylpyrroles and 3‐benzylindoles
Authors: Sharma Ratnesh , Chouhan Mangilal , Sood Divya , Nair Vipin A.
Published: January 2011

One‐pot regioselective benzylation of pyrroles and indoles using zirconium tetrachloride is discussed. This has been achieved by in‐situ generation of di(1H‐pyrrol‐1‐yl)zirconium(IV) chloride and di(1H‐indol‐1‐yl)zirconium(IV) chloride. It was observed that benzylation reactions of these complexes using n‐BuLi occurred at C‐2 position for pyrrole and C‐3 for indole. Copyright © 2011 John Wiley & Sons, Ltd.
Photopolymerization characteristics of bisbenzo[1,3]dioxol‐5‐ylmethanone as an initiator
Authors: Cui Rong , Wang Kemin , Ma Guiping , Qian Bin , Yang Jianxin , Yu Qiang , Nie Jun
Published: January 2011

Bisbenzo[1,3]dioxol‐5‐ylmethanone (BBDOM), a type of hydrogen‐abstraction photoinitiator, exhibited redshifted maximal absorption in comparison with benzophenone (BP) according to ultraviolet–visible absorption spectroscopy. The kinetics of photopolymerization of the photoinitiator in different systems was studied with real‐time infrared spectroscopy. The concentration of BBDOM, the components of the initiator, and the functionality of the monomer had great effects on the kinetics of photopolymerization. The results show that BBDOM is a more effective photoinitiator than BP. BBDOM consists of cyclic acetals that are widely distributed in nature, and with BBDOM, the use of large numbers of amines can be avoided in the system without the requirement of an additional hydrogen donor. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Theoretical analysis of fracture of tetra‐needle‐like ZnO whisker in polymer composite
Authors: Zhu Shibu , Jiang Man , Qiu Jianhui , Zhou Zuowan , Wang Yong , Fan Ximei
Published: January 2011

It is of practical importance to develop the tetra‐needle‐shaped ZnO whisker (T‐ZnOw)‐reinforced polymer composites that have isotropic properties. To give a guidance of material design and manufacture, it is necessary to have a theoretical analysis of the fracture mechanisms of this peculiar structure fiber in polymer composites. Based on previous investigations of the T‐ZnOw‐reinforced polymer composites, and from the viewpoint of materials mechanics, here we analyzed the distribution of stresses on different points of the tetra‐ needle‐like crystal whiskers in a composite and calculated the total stress at the connection point. The results indicate that the stress on the connection point is proportional to the exerting force and correlates with the dimension, the size, and the location of the whiskers. According to the theoretical derivations, it was found that the stress at the connection point of the T‐ZnOw is much larger than that at the others, leading to breakage on that point mainly or wholly, which is in accordance with the experimental observations. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Aminolysis of poly(ethylene terephthalate) wastes based on sunlight and utilization of the end product [bis(2‐hydroxyethylene) terephthalamide] as an ingredient in the anticorrosive paints for the protection of steel structures
Authors: Tawfik Magda E. , Ahmed Nivin M. , Eskander Samir B.
Published: January 2011

The increasing demand for poly(ethylene terephthalate) (PET) polymer, the simultaneous shortage in landfill disposal spaces, and known problems associated with PET waste specifically (e.g., its nonbiodegradability and huge accumulation) are challenges with which mankind must cope nowadays. In this study, PET postconsumer bottle wastes were cut to very small slides and then subjected to an aminolysis process with ethanol amine as a degradative agent in the presence of one catalyst from three used in this study. These catalysts were dibutyl tin oxide, sodium acetate, and cetyltrimethyl ammonium bromide. The reaction was performed in sunlight: a beneficial, clean, cheap, and renewable source of energy. The end product, which was a white precipitate of bis(2‐hydroxyethylene) terephthalamide, was subjected to spectrophotometric and thermal analyses. The product was characterized to asses its suitability for use in pigments in anticorrosive paint formulations. In general, this process was a green, environmentally friendly degradation based on the utilization of solar energy for the aminolysis reaction using simple, cheap, available chemicals as catalysts. The originality of this study was derived from the use of waste materials to yield a product with beneficial applications in the field of corrosion inhibition. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Exacerbation of type II collagen–induced arthritis in apolipoprotein E–deficient mice in association with the expansion of Th1 and Th17 cells
Authors: Postigo Jorge , Genre Fernanda , Iglesias Marcos , Fernández‐Rey Maigualida , Buelta Luis , Carlos Rodríguez‐Rey José , Merino Jesús , Merino Ramón
Published: January 2011

Objective

To explore the bidirectional relationship between the development of rheumatoid arthritis (RA) and atherosclerosis using bovine type II collagen (CII)–immunized B10.RIII apoE−/− mice, a murine model of spontaneous atherosclerosis and collagen‐induced arthritis (CIA).

Methods

Male B10.RIII apoE−/− mice and wild‐type controls were immunized with 150 μg of CII emulsified in Freund's complete adjuvant (CFA). The clinical, radiologic, and histopathologic severity of CIA, the levels of circulating IgG1 and IgG2a anti‐CII antibodies, the expression of proinflammatory and antiinflammatory cytokines in the joints, and the percentages of Th1, Th17, and Treg lymphocytes in the draining lymph nodes were evaluated during CIA induction. In addition, the size of atherosclerotic lesions was assessed in these mice 8 weeks after CIA induction.

Results

B10.RIII apoE−/− mice that were immunized with CII and CFA developed an exacerbated CIA that was accompanied by increased joint expression of multiple proinflammatory cytokines and by the expansion in the draining lymph nodes of Th1 and Th17 cells. In contrast, the size of vascular lesions in B10.RIII apoE−/− mice was not affected by the development of CIA.

Conclusion

Our findings indicate that a deficiency in apolipoprotein E and/or its consequences in cholesterol metabolism act as accelerating factors in autoimmunity by promoting Th1 and Th17 inflammatory responses.
The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice
Authors: Sekine Hideharu , Kinser Ting Ting Hsieh , Qiao Fei , Martinez Efrain , Paulling Emily , Ruiz Phillip , Gilkeson Gary S. , Tomlinson Stephen
Published: January 2011

Objective

Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (ICs) and apoptotic cells and its role in inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. The aim of this study was to investigate the effect of a new targeted inhibitor of the alternative pathway, CR2‐fH, on lupus‐like renal disease in MRL/lpr mice.

Methods

Mice were treated with either saline, CR2‐fH, CR2‐Crry (which inhibits all complement pathways), or soluble CR2 (sCR2; C3d‐binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs, and C3. Urinary excretion of albumin was also determined, and kidneys were collected at 23 weeks for histologic evaluation.

Results

Treatment with CR2‐fH or CR2‐Crry improved survival and significantly reduced proteinuria, glomerular C3 deposition, and the level of circulating ICs. CR2‐fH, but not CR2‐Crry, also significantly reduced glomerulonephritis, expression of serum anti–double‐stranded DNA (anti‐dsDNA) antibodies, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced the levels of anti‐dsDNA antibodies and circulating ICs and reduced glomerular deposition of IgG, C1q, and C3, although there was no significant reduction in glomerulonephritis, proteinuria, or mortality.

Conclusion

Targeted and selective inhibition of the alternative complement pathway is an effective treatment of murine lupus and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact and indicate distinct roles for the classical and alternative pathways of complement in disease progression. The sCR2‐targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity.
Characterization of CCL19 and CCL21 in rheumatoid arthritis
Authors: Pickens Sarah R. , Chamberlain Nathan D. , Volin Michael V. , Pope Richard M. , Mandelin Arthur M. , Shahrara Shiva
Published: January 2011

Objective

To characterize the expression of CCL19 and CCL21 in rheumatoid arthritis (RA) synovial tissue (ST) and to examine their regulation and pathogenetic role in macrophages and RA ST fibroblasts.

Methods

Expression of CCL19 and CCL21 in RA and normal ST was demonstrated by immunohistochemistry analysis. CCL19 and CCL21 levels in synovial fluid (SF) from patients with osteoarthritis (OA), juvenile idiopathic arthritis, psoriatic arthritis (PsA), and RA were quantified by enzyme‐linked immunosorbent assay (ELISA). Regulation of CCL19 and CCL21 expression in in vitro–differentiated RA peripheral blood macrophages as well as RA ST fibroblasts was determined by real‐time reverse transcription–polymerase chain reaction. Proangiogenic factor production in CCL19‐ and CCL21‐activated in vitro–differentiated peripheral blood macrophages and RA ST fibroblasts was examined by ELISA.

Results

CCL19 and CCL21 were elevated in RA ST compared to tissue from normal controls. Levels of CCL19 and CCL21 were greatly increased in RA and PsA SF versus OA SF. In RA macrophages and fibroblasts, expression of CCL19 was increased by stimulation with lipopolysaccharide, tumor necrosis factor α (TNFα), and interleukin‐1β (IL‐1β). However, CCL21 expression was modulated only by IL‐1β in RA fibroblasts, and by TNFα and RA SF in RA macrophages. CCL19 and CCL21 activation induced vascular endothelial growth factor and angiotensin I (Ang I) production in RA ST fibroblasts and secretion of IL‐8 and Ang I from macrophages.

Conclusion

The findings of the present study identify, for the first time, regulators of CCL19 and CCL21 in RA fibroblasts and in vitro–differentiated RA peripheral blood macrophages and demonstrate a novel role of CCL19/CCL21 in angiogenesis in RA.
B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six‐month, national, multicenter, open‐label study
Authors: Sellam Jérémie , Hendel‐Chavez Houria , Rouanet Stéphanie , Abbed Karim , Combe Bernard , Le Loët Xavier , Tebib Jacques , Sibilia Jean , Taoufik Yassine , Dougados Maxime , Mariette Xavier
Published: January 2011

Objective

To examine whether serum B cell markers can predict response to rituximab, a B cell–depleting monoclonal antibody, in patients with refractory rheumatoid arthritis (RA).

Methods

This rituximab re‐treatment dose study (SMART [eSsai MAbthera sur la dose de Re‐Traitement]) involved 208 patients with refractory RA. Serum markers of B cell activation (anti–cyclic citrullinated peptide [anti‐CCP] antibodies, rheumatoid factor [RF], serum IgG, IgA, and IgM levels, serum κ and λ free light chains, and serum BAFF) were assessed before the first rituximab cycle (1,000 mg on days 1 and 15). Univariate and multivariate analyses were performed to identify factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks.

Results

There were 149 responders (72%). Two baseline factors were associated with a EULAR response at 24 weeks in multivariate analysis: the presence of anti‐CCP antibodies or RF (odds ratio 3.5 [95% confidence interval 1.6–7.6]) and a serum IgG concentration above normal (odds ratio 2.11 [95% confidence interval 1.02–4.33]), with synergy between them (odds ratio 6.0 [95% confidence interval 2.2–16.2]).

Conclusion

The presence of RF or anti‐CCP antibodies and elevated IgG are 2 simple biomarkers that can be used routinely before therapy to predict response to rituximab in patients with refractory RA.
Long‐term clinical profile of children with the low‐penetrance R92Q mutation of the TNFRSF1A gene
Authors: Pelagatti M. A. , Meini A. , Caorsi R. , Cattalini M. , Federici S. , Zulian F. , Calcagno G. , Tommasini A. , Bossi G. , Sormani M. P. , Caroli F. , Plebani A. , Ceccherini I. , Martini A. , Gattorno M.
Published: January 2011

Objective

To analyze the long‐term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor–associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA).

Methods

The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high‐performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50‐item Child Health Questionnaire was used to assess health‐related quality of life (HRQOL).

Results

The frequency of typical TRAPS‐related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self‐resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations.

Conclusion

Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.
Metal‐Free Dehydration of Glucose to 5‐(Hydroxymethyl)furfural in Ionic Liquids with Boric Acid as a Promoter
Authors: Ståhlberg Tim , Rodriguez‐Rodriguez Sergio , Fristrup Peter , Riisager Anders
Published: January 2011

The dehydration of glucose and other hexose carbohydrates to 5‐(hydroxymethyl)furfural (HMF) was investigated in imidazolium‐based ionic liquids with boric acid as a promoter. A yield of up to 42 % from glucose and as much as 66 % from sucrose was obtained. The yield of HMF decreased as the concentration of boric acid exceeded one equivalent, most likely as a consequence of stronger fructose–borate chelate complexes being formed. Computational modeling with DFT calculations confirmed that the formation of 1:1 glucose–borate complexes facilitated the conversion pathway from glucose to fructose. Deuterium‐labeling studies elucidated that the isomerization proceeded via an ene–diol mechanism, which is different to that of the enzyme‐catalyzed isomerization of glucose to fructose. The introduced non‐metal system containing boric acid provides a new direction in the search for catalyst systems allowing efficient HMF formation from biorenewable sources.
Self‐Assembly Approach toward Chiral Bimetallic Catalysts: Bis‐Urea‐Functionalized (Salen)Cobalt Complexes for the Hydrolytic Kinetic Resolution of Epoxides
Authors: Park Jongwoo , Lang Kai , Abboud Khalil A. , Hong Sukwon
Published: January 2011

A series of novel bis‐urea‐functionalized (salen)Co complexes has been developed. The complexes were designed to form self‐assembled structures in solution through intermolecular urea–urea hydrogen‐bonding interactions. These bis‐urea (salen)Co catalysts resulted in rate acceleration (up to 13 times) in the hydrolytic kinetic resolution (HKR) of rac‐epichlorohydrin in THF by facilitating cooperative activation, compared to the monomeric catalyst. In addition, one of the bis‐urea (salen)CoIII catalyst efficiently resolves various terminal epoxides even under solvent‐free conditions by requiring much shorter reaction time at low catalyst loading (0.03–0.05 mol %). A series of kinetic/mechanistic studies demonstrated that the self‐association of two (salen)Co units through urea–urea hydrogen bonds was responsible for the observed rate acceleration. The self‐assembly study with the bis‐urea (salen)Co by FTIR spectroscopy and with the corresponding (salen)Ni complex by 1H NMR spectroscopy showed that intermolecular hydrogen‐bonding interactions exist between the bis‐urea scaffolds in THF. This result demonstrates that self‐assembly approach by using non‐covalent interactions can be an alternative and useful strategy toward the efficient HKR catalysis.
Frontline treatment of localized osteosarcoma without methotrexate
Authors: Daw Najat C. , Neel Michael D. , Rao Bhaskar N. , Billups Catherine A. , Wu Jianrong , Jenkins Jesse J. , Quintana Juan , Luchtman‐Jones Lori , Villarroel Milena , Santana Victor M.
Published: January 2011

BACKGROUND:

The standard treatment of osteosarcoma includes cisplatin and high‐dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin‐based regimens and caused less toxicity. To build on this experience, the authors conducted a multi‐institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma.

METHODS:

Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration‐time curve of 8 mg/mL × min on Day 1) and ifosfamide (at a dose of 2.65 g/m2 daily ×3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m2 daily ×3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m2 daily ×2 days) combined with ifosfamide or carboplatin.

RESULTS:

A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (>90% tumor necrosis) to preoperative chemotherapy. The estimated 5‐year event‐free survival rate was 66.7% ± 7.0% for the OS99 trial compared with 66.0% ± 6.8% for the OS91 trial (P = .98). The estimated 5‐year survival rate was 78.9% ± 6.3% for the OS99 trial and 74.5% ± 6.3% for the OS91 trial (P = .40).

CONCLUSIONS:

The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin‐containing or HDMTX‐containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX. Cancer 2011. © 2011 American Cancer Society.
How does patient‐clinician information engagement influence self‐reported cancer‐related problems?
Authors: Tan Andy S. L. , Bourgoin Angel , Gray Stacy W. , Armstrong Katrina , Hornik Robert C.
Published: January 2011

BACKGROUND:

Past research has linked patient‐physician communication with improved emotional, physical, and social health. One component of communication, patient‐clinician information engagement (PCIE), predicts improved short‐term patient‐reported outcomes, such as treatment satisfaction, through perceptions of feeling informed. However, to the authors' knowledge, the relation between PCIE and longer term cancer‐related problems has not been examined previously. The authors examined the influence of PCIE on self‐reported problems associated with cancer diagnosis and treatment based on a longitudinal survey among a randomly selected sample from the 2005 Pennsylvania Cancer Registry.

METHODS:

In total, 1293 respondents were surveyed who were diagnosed with colorectal, breast, or prostate cancers during 2006 and 2007. The baseline response rate was 64%, and the retention rate was 65%. The authors predicted an index of cancer‐related problems at 1‐year follow‐up with the baseline cancer‐related problem index and PCIE, controlling for demographic and clinical factors using regression analyses. The mean age of participants was 65 years, approximately 50% were women, and 86% were white.

RESULTS:

Having more cancer‐related problems and PCIE at baseline significantly predicted more cancer‐related problems at follow‐up. In addition, baseline cancer‐related problems and PCIE interacted significantly (P = .01): PCIE was associated with more cancer‐related problems at follow‐up among participants who reported more symptoms rather than fewer symptoms at baseline.

CONCLUSIONS:

If respondents reported engaging more with their physicians at baseline, then they reported experiencing more cancer‐related issues at follow‐up; this pattern was stronger among those who reported more baseline problems. The current results indicated that increased discussion of cancer information with physicians may maintain the salience of these problems in cancer survivors' minds over time. Cancer 2011. © 2011 American Cancer Society.
Clinical features and outcomes in patients with extraskeletal ewing sarcoma
Authors: Applebaum Mark A. , Worch Jennifer , Matthay Katherine K. , Goldsby Robert , Neuhaus John , West Daniel C. , DuBois Steven G.
Published: January 2011

BACKGROUND:

Ewing sarcoma can arise in either bone or soft tissue. The purpose of this study was to investigate whether patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES).

METHODS:

Patients <40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor reported to the United States Surveillance, Epidemiology, and End Results Program database from 1973 to 2007 were evaluated based on skeletal (n = 1519) versus extraskeletal (n = 683) site of origin. Patient characteristics were compared using Fisher exact tests. Overall survival was estimated via the Kaplan‐Meier method and compared using log‐rank tests and Cox proportional hazard models.

RESULTS:

Patients with EES had a higher mean age (19.5 vs 16.3 years; P < .001) and were less likely to be male (53.4% vs 63.3%; P < .001) or white (84.8% vs 92.5%; P < .001) compared with patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs 54.2%; P = .001) but were less likely to arise specifically in the pelvis (19.8% vs 26.6%; P < .001). Metastatic status or tumor size did not differ by group. Five‐year overall survival was superior for localized EES compared with localized skeletal tumors (69.7% vs 62.6%; P = .02). The hazard ratio for death in patients with localized skeletal tumors compared with localized EES was 2.36 (95% confidence interval, 1.61‐3.44) beyond 24 months from initial diagnosis.

CONCLUSIONS:

Patient characteristics and outcomes differ among patients with EES compared with patients with skeletal Ewing sarcoma. These findings may have important implications for patient care. Cancer 2011. © 2011 American Cancer Society.
Association between somatostatin receptor 5 gene polymorphisms and pancreatic cancer risk and survival
Authors: Li Donghui , Tanaka Motofumi , Brunicardi F. Charles , Fisher William E. , Gibbs Richard A , Gingras Marie‐Claude
Published: January 2011

BACKGROUND:

Somatostatin (SST) inhibited cell proliferation and negatively regulated the release of growth hormones by means of specific receptors (SSTR). Genetic variation in SSTR had been associated with risk of human cancers but had never been investigated in pancreatic cancer.

METHODS:

In this retrospective study the SSTR5 gene in paired tumor and blood samples from 33 pancreatic adenocarcinoma patients using the Sanger method were sequenced. Three single nucleotide polymorphisms (SNPs) in samples from 863 patients with pancreatic ductal adenocarcinoma and 876 healthy controls using the TaqMan method were analyzed. The associations between gene polymorphisms and pancreatic cancer risk and survival were analyzed by multivariate logistic regression and Cox proportional hazard models, respectively.

RESULTS:

No somatic mutations were identified, but 3 nonsynonymous SSTR5 SNPs (P109S, L48M, and P335L) in pancreatic tumors were identified. The SSTR5 P109S variant allele was associated with a 1.62‐fold increased risk of pancreatic cancer (95% confidence interval [CI]: 1.08‐2.43, P = 0.019). Furthermore, the SSTR5 L48M AC variant and smoking had a joint effect on pancreatic cancer risk (pinteraction = 0.035). The odds ratios (95% confidence intervals) were 0.58 (0.34‐0.97), 1.49 (1.18‐1.89), and 2.27 (1.35‐3.83) for the variant genotype alone, smoking alone, and both factors, respectively, compared with no factors. Finally, SSTR5 P335L CC and P109S CC combined were associated with lower overall survival durations in patients with resectable disease.

CONCLUSIONS:

These data suggest that SSTR5 genetic variants play a role in pancreatic cancer development and progression. Cancer 2011. © 2011 American Cancer Society.