bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Convergent Total Synthesis of the Telomerase Inhibitor (±)‐γ‐Rubromycin
Authors: Wilsdorf Michael , Reissig Hans‐Ulrich 
Published: March 2014

AbstractThe total synthesis of the human telomerase inhibitor γ‐rubromycin in its racemic form was accomplished in 3.8 % overall yield. The key feature of this synthesis is an efficient acid‐catalyzed spiroketalization for the construction of the spiroketal core. The required electronically well‐balanced spiroketal precursor was obtained by the convergent assembly of a naphthyl‐substituted aldehyde, an α‐methoxyallyl‐γ‐silyl‐substituted phosphonate as the central C3 building block, and a highly functionalized aryl Grignard reagent. Another key feature is the late‐stage construction of the isocoumarin moiety and a simultaneous protodesilylation furnishing the known methyl aryl ether protected precursor of γ‐rubromycin.
Significance of Preradiographic Magnetic Resonance Imaging Lesions in Persons at Increased Risk of Knee Osteoarthritis
Authors: Sharma Leena , Chmiel Joan S. , Almagor Orit , Dunlop Dorothy , Guermazi Ali , Bathon Joan M. , Eaton Charles B. , Hochberg Marc C. , Jackson Rebecca D. , Kwoh C. Kent , Mysiw W. Jerry , Crema Michel D. , Roemer Frank W. , Nevitt Michael C. 
Published: March 2014

ObjectiveLittle is known about early knee osteoarthritis (OA). The significance of lesions on magnetic resonance imaging (MRI) in older persons without radiographic OA is unclear. Our objectives were to determine the extent of tissue pathology by MRI and evaluate its significance by testing the following hypotheses: cartilage damage, bone marrow lesions, and meniscal damage are associated with prevalent frequent knee symptoms and incident persistent symptoms; bone marrow lesions and meniscal damage are associated with incident tibiofemoral (TF) cartilage damage; and bone marrow lesions are associated with incident patellofemoral (PF) cartilage damage.MethodsIn a cohort study of 849 Osteoarthritis Initiative (OAI) participants who had a bilateral Kellgren/Lawrence (K/L) score of 0, we assessed cartilage damage, bone marrow lesions, and meniscal damage using the MRI OA Knee Score, as well as prevalent frequent knee symptoms, incident persistent symptoms, and incident cartilage damage. Multiple logistic regression (one knee per person) was used to evaluate associations between MRI lesions and each of these outcomes.ResultsOf the participants evaluated, 76% had cartilage damage, 61% had bone marrow lesions, 21% had meniscal tears, and 14% had meniscal extrusion. Cartilage damage (any; TF and PF), bone marrow lesions (any; TF and PF), meniscal extrusion, and body mass index (BMI) were associated with prevalent frequent symptoms. Cartilage damage (isolated PF; TF and PF), bone marrow lesions (any; isolated PF; TF and PF), meniscal tears, and BMI were associated with incident persistent symptoms. Hand OA, but no individual lesion type, was associated with incident TF cartilage damage, and bone marrow lesions (any; any PF) with incident PF damage. Having more lesion types was associated with a greater risk of outcomes.ConclusionMRI‐detected lesions are not incidental and may represent early disease in persons at increased risk of knee OA.
Modifications of Gait as Predictors of Natural Osteoarthritis Progression in STR/Ort Mice
Authors: Poulet Blandine , de Souza Roberto , Knights Chancie B. , Gentry Clive , Wilson Alan M. , Bevan Stuart , Chang Yu‐Mei , Pitsillides Andrew A. 
Published: March 2014

ObjectiveOsteoarthritis (OA) is a common chronic disease for which disease‐modifying therapies are not currently available. Studies to seek new targets for slowing the progress of OA rely on mouse models, but these do not allow for longitudinal monitoring of disease development. This study was undertaken to determine whether gait can be used to measure disease severity in the STR/Ort mouse model of spontaneous OA and whether gait changes are related to OA joint pain.MethodsGait was monitored using a treadmill‐based video system. Correlations between OA severity and gait at 3 treadmill speeds were assessed in STR/Ort mice. Gait and pain behaviors of STR/Ort mice and control CBA mice were analyzed longitudinally, with monthly assessments.ResultsThe best speed to identify paw area changes associated with OA severity in STR/Ort mice was found to be 17 cm · seconds−1. Paw area was modified with age in CBA and STR/Ort mice, but this began earlier in STR/Ort mice and correlated with the onset of OA at 20 weeks of age. In addition, task noncompliance appeared at 20 weeks. Surprisingly, STR/Ort mice did not show any signs of pain with OA development, even when treated with the opioid antagonist naloxone, but did exhibit normal pain behaviors in response to complete Freund's adjuvant–induced arthritis.ConclusionThe present results identify an animal model in which OA severity and OA pain can be studied in isolation from one another. The findings suggest that paw area and treadmill noncompliance may be useful tools to longitudinally monitor nonpainful OA development in STR/Ort mice. This will help in providing a noninvasive means of assessing new therapies to slow the progression of OA.
A Phase II Randomized Study of Subcutaneous Ixekizumab, an Anti–Interleukin‐17 Monoclonal Antibody, in Rheumatoid Arthritis Patients Who Were Naive to Biologic Agents or Had an Inadequate Response to Tumor Necrosis Factor Inhibitors
Authors: Genovese Mark C. , Greenwald Maria , Cho Chul‐Soo , Berman Alberto , Jin Ling , Cameron Gregory S. , Benichou Olivier , Xie Li , Braun Daniel , Berclaz Pierre‐Yves , Banerjee Subhashis 
Published: March 2014

ObjectiveTo evaluate ixekizumab, an anti–interleukin‐17A (anti–IL‐17A) monoclonal antibody, in 2 populations of rheumatoid arthritis (RA) patients: biologics‐naive patients and patients with an inadequate response to tumor necrosis factor (TNF) inhibitors.MethodsIn this phase II, randomized, double‐blind study, placebo or ixekizumab was administered subcutaneously to 260 biologics‐naive patients and 188 patients with an inadequate response to TNF inhibitors at weeks 0, 1, 2, 4, 6, 8, and 10 with concomitant disease‐modifying antirheumatic drugs. The primary objective was to determine the dose‐response relationship of ixekizumab as measured by the proportion of biologics‐naive patients meeting the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.ResultsUsing a logistic regression model defined a priori, a statistically significant dose‐response relationship as measured by ACR20 response rates at week 12 was detected in biologics‐naive patients (P = 0.031). For patients with an inadequate response to TNF inhibitors, ACR20 responses at week 12 were significantly better with ixekizumab than placebo (P < 0.05). Decreases in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP), Clinical Disease Activity Index (CDAI), and CRP level from baseline were observed at week 12 in the ixekizumab groups in both populations (P < 0.05 versus placebo). Onset of action was rapid in some dose groups in both populations, with improvements in the ACR20, DAS28‐CRP, CRP levels, and CDAI observed by day 3 (P < 0.05). Adverse events occurred with similar frequencies overall in the ixekizumab and placebo groups. Infections were more frequent with ixekizumab than placebo (biologics‐naive 25% versus 19%; inadequate responders to TNF inhibitors 27% versus 25%). No mycobacterial or invasive fungal infections were reported.ConclusionIxekizumab improved RA signs and symptoms in RA patients who were either naive to biologics treatment or had an inadequate response to TNF inhibitors. The safety profile was similar to that of other biologic agents, with no unexpected safety concerns.
Antibodies to Endothelial Cell Growth Factor and Obliterative Microvascular Lesions in the Synovium of Patients With Antibiotic‐Refractory Lyme Arthritis
Authors: Londoño Diana , Cadavid Diego , Drouin Elise E. , Strle Klemen , McHugh Gail , Aversa John M. , Steere Allen C. 
Published: March 2014

ObjectiveEndothelial cell growth factor (ECGF) was recently identified as the first autoantigen known to be a target of T cell and B cell responses in ∼20% of patients with antibiotic‐refractory Lyme arthritis. The goal of the current study was to look for a pathologic correlate between ECGF autoantibody responses and histologic findings in synovial tissue.MethodsSynovial tissue was examined from 14 patients with antibiotic‐refractory Lyme arthritis and 6 patients with other forms of chronic inflammatory arthritis, primarily rheumatoid arthritis. The tissue sections were subjected to chemical and immunostaining, and IgG antibody responses to ECGF were determined by enzyme‐linked immunosorbent assay (ELISA). Each finding was ranked for statistical analysis.ResultsIn each disease, synovial tissue showed synovial hypertrophy, vascular proliferation, immune cell infiltrates, and fibrosis. However, among the 14 patients with antibiotic‐refractory arthritis, 8 (57%) had obliterative microvascular lesions in the tissue, compared with none of the 6 patients with other forms of chronic inflammatory arthritis (P = 0.04). Among the patients with Lyme arthritis, 5 (36%) had autoantibody responses to ECGF, and all 5 had obliterative lesions, as compared with only 3 of 9 patients who lacked ECGF antibody responses (P = 0.009). Moreover, the magnitude of ECGF antibody responses correlated directly with the extent of obliterative lesions (P = 0.02) and with greater vascularity in the tissue (P = 0.05).ConclusionThe correlations of ECGF autoantibody reactivity with obliterative microvascular lesions imply that these autoantibodies may be involved in the obliterative process, suggesting that anti‐ECGF antibodies have specific pathologic consequences in the synovial tissue of patients with antibiotic‐refractory Lyme arthritis.
Bone‐ and Cartilage‐Protective Effects of a Monoclonal Antibody Against Colony‐Stimulating Factor 1 Receptor in Experimental Arthritis
Authors: Toh Myew‐Ling , Bonnefoy Jean‐Yves , Accart Nathalie , Cochin Sandrine , Pohle Sandy , Haegel Hélène , De Meyer Micael , Zemmour Christophe , Preville Xavier , Guillen Christine , Thioudellet Christine , Ancian Philippe , Lux Anja , Sehnert Bettina , Nimmerjahn Falk , Voll Reinhard E. , Schett Georg 
Published: March 2014

ObjectiveColony‐stimulating factor 1 receptor (CSF‐1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF‐1R expression in human RA as well as the efficacy of a specific anti–CSF‐1R monoclonal antibody (AFS98) in 2 different animal models of RA.MethodsCSF‐1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen‐induced arthritis (CIA) and serum‐transfer arthritis.ResultsCSF‐1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast‐like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF‐1R+. In mice, blockade of CSF‐1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF‐1R did not affect inflammation in passive serum‐transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr‐1− monocytes.ConclusionCSF‐1R was broadly expressed in human RA. Blockade of CSF‐1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF‐1R as a therapeutic target in RA.
Disposition of d‐penicillamine, a promising drug for preventing alcohol‐relapse. Influence of dose, chronic alcohol consumption and age: studies in rats
Authors: Orrico Alejandro , Martí‐Prats Lucía , Cano‐Cebrián M. José , Polache Ana , Zornoza Teodoro , Granero Luis 
Published: March 2014

ABSTRACTPharmacokinetic studies concerning d‐penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose d‐penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on d‐penicillamine disposition in order to guide future clinical studies on the anti‐relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on d‐penicillamine disposition, whereas studies 2 and 3 evaluated, respectively, the influence of chronic alcohol consumption and age. Rapid intravenous administrations of 2, 10 and 30 mg/kg of d‐penicillamine were performed using young or adult ethanol‐naïve rats or adult ethanol‐experienced (subjected to a long‐term ethanol self‐administration protocol) rats. Pharmacokinetic parameters were derived from the biexponential model. Statistical analysis of CL, normalized AUC0∞, V1 and k10 revealed that disposition, in the range plasma concentrations assayed, is non‐linear both in young ethanol‐naïve and in adult ethanol‐experienced rats. Notably, no significant changes in t1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t1/2. d‐Penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non‐linear, the lack of significant alterations of the t1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters d‐penicillamine disposition but, again, does not modify t1/2. Copyright © 2014 John Wiley & Sons, Ltd.
Dietary intake of choline and neural tube defects in Mexican Americans
Authors: Lavery Amy M. , Brender Jean D. , Zhao Hongwei , Sweeney Anne , Felkner Marilyn , Suarez Lucina , Canfield Mark A. 
Published: March 2014

BackgroundLow maternal intake of dietary choline and betaine (a choline derivative) has recently been investigated as a possible risk factor for neural tube defects (NTDs)MethodsThis case‐control study examined the NTD risk associated with choline and betaine in 409 Mexican‐American women who gave birth during 1995 to 2000 in the 14‐county border region of TexasResultsUsing data from the food frequency questionnaire and the lowest quartiles of intake as the reference categories, a protective association was suggested between higher intakes of choline and betaine and NTD risk although the 95% confidence intervals for all risk estimates included 1.0. For choline intake in the second, third, and fourth quartiles, adjusted odds ratios were 1.2, 0.80, and 0.89, respectively. Betaine appeared more protective with odds ratios of 0.62, 0.73, and 0.61, respectively, for the second, third, and fourth quartiles of intakeConclusionStudy findings suggest that dietary betaine may help to prevent NTDs. Birth Defects Research (Part A) 100:463–471, 2014. © 2014 Wiley Periodicals, Inc.
Characterization of the interaction of a mono‐6‐thio‐β‐cyclodextrin‐capped CdTe quantum dots–methylene blue/methylene green system with herring sperm DNA using a spectroscopic approach
Authors: Shen Yizhong , Liu Shaopu , Wang Lei , Yin Pengfei , He Youqiu 
Published: March 2014

ABSTRACTNovel, water‐soluble CdTe quantum dots (QDs) capped with β‐cyclodextrin (β‐CD) and ~ 4.0 nm in diameter were synthesized in aqueous solution, and characterized using transmission electron microscopy (TEM). A fluorescence‐sensing system based on the photoinduced electron transfer (PET) of (mono‐6‐thio‐β‐CD)–CdTe QDs was then designed to measure the interaction of phenothiazine dyes [methylene blue (MB) and methylene green (MG)] with herring sperm DNA (hsDNA). This fluorescence‐sensing system was based on a fluorescence “OFF–ON” mode. First, MB/MG adsorbed on the surface of (mono‐6‐thio‐β‐CD)–CdTe QDs effectively quenches the fluorescence of (mono‐6‐thio‐β‐CD)–CdTe QDs through PET. Then, addition of hsDNA restores the fluorescence intensity of (mono‐6‐thio‐β‐CD)–CdTe QDs, because hsDNA can bind with MB/MG and remove it from the as‐prepared (mono‐6‐thio‐β‐CD)–CdTe QDs. In addition, detailed reaction mechanisms of the (mono‐6‐thio‐β‐CD)–CdTe QDs–MB/MG–hsDNA solution system were studied using optical methods, by comparison with the TGA–CdTe QDs–MB/MG–hsDNA solution system. Copyright © 2014 John Wiley & Sons, Ltd.
The pharmacokinetic study of sinomenine, paeoniflorin and paeonol in rats after oral administration of a herbal product Qingfu Guanjiesu capsule by HPLC
Authors: Xie Ying , Jiang Zhi‐Hong , Zhou Hua , Ma Wen‐Zhe , Wong Yuen‐Fan , Liu Zhong‐Qiu , Liu Liang 
Published: March 2014

ABSTRACTAn accurate and reliable high‐performance liquid chromatography–diode array detector (HPLC‐DAD) method was developed and validated for determination of sinomenine (SI), paeoniflorin (PF) and paeonol (PA), which was further applied to assess the pharmacokinetics of SI, PF and PA in an anti‐arthritic herbal product, Qingfu Guanjieshu (QFGJS) capsule, in rats. Successful separation was achieved with a C18 column and a mobile phase composed of acetonitrile and aqueous phase (containing 0.1% formic acid, adjusted with triethylamine to pH 3.5 ± 0.2). The method was validated with excellent precision, accuracy, recovery and stability in calibration ranges from 0.06 to 11.62 µg/mL for SI, from 0.09 to 35.70 µg/mL for PF, and from 0.15 to 4.53 µg/mL for PA (with r2 > 0.999 for all three compounds). Our results showed that absorption of PF after administration of QFGJS was similar to that after oral administration of PF alone; the absorption of SI was decreased while the absorption of PA was increased after giving QFGJS orally compared with pure compounds. We may conclude that pharmacokinetic studies of complex herbal products are not only necessary but also feasible by using representative bioactive chemicals as indicators of establishing quality control standards and of determining pharmacokinetic behavior of herbal medicines. Copyright © 2014 John Wiley & Sons, Ltd.
Functional Investigations of Thromboxane Synthase (CYP5A1) in Lipid Bilayers of Nanodiscs
Authors: Das Aditi , Varma Snehita Sri , Mularczyk Christopher , Meling Daryl D. 
Published: March 2014

AbstractCYP5A1 is a membrane‐associated cytochrome P450 that metabolizes the cyclooxygenase product prostaglandin (PGH2) into thromboxane A2 (TXA2), a potent inducer of vasoconstriction and platelet aggregation. Although CYP5A1 is an ER‐bound protein, the role of membranes in modulating the thermodynamics and kinetics of substrate binding to this protein has not been elucidated. In this work, we incorporated thromboxane synthase into lipid bilayers of nanodiscs for functional studies. We measured the redox potential of CYP5A1 in nanodiscs and showed that the redox potential is within a similar range of other drug‐metabolizing P450 enzymes in membranes. Further, we showed that binding of substrate to CYP5A1 can induce conformational changes in the protein that block small‐molecule ligand egress by measuring the kinetics of cyanide binding to CYP5A1 as a function of substrate concentration. Notably, we observed that sensitivity to cyanide binding was different for two substrate analogues, U44069 and U46619, thus indicating that they bind differently to the active site of CYP5A1. We also characterized the effects of the different lipids on CYP5A1 catalytic activity by using nanodiscs to create unary, binary, and ternary lipid systems. CYP5A1 activity increased dramatically in the presence of charged lipids POPS and POPE, as compared to the unary POPC system. These results suggest the importance of lipid composition on modulating the activity of CYP5A1 to increase thromboxane formation.
Arginine Arrangement of Bacteriophage λ N‐Peptide Plays a Role as a Core Motif in GNRA Tetraloop RNA Binding
Authors: Furusawa Hiroyuki , Fukusho Shinobu , Okahata Yoshio 
Published: March 2014

AbstractA simple α‐helical N‐model‐peptide was designed to investigate the role of the arginine‐rich motif of bacteriophage λ N‐peptide in selective binding with boxB RNA. The five‐arginine arrangement of native N‐peptide was retained; all other residues were replaced with alanine. In vitro selection of RNA (30 random‐nucleotide region) was carried out with N‐model‐peptide immobilized on a 27 MHz quartz‐crystal microbalance (QCM). Selected RNAs were evaluated on the same QCM plate to obtain binding constants (Ka=107–108 M−1). Many selected RNAs contained GNR(N)A‐type loops (similar to the boxB RNA motif recognized by the native N‐peptide). Fragments and minimal RNAs containing the GNRA‐type loop also bound to N‐model‐peptide (Ka=106–107 M−1). The RNA recognition specificity of the peptide was studied by changing the “closing” U–A base pair and one base in the tetraloop of the RNA aptamers, and by peptide mutations (18th residue of N‐model‐peptide). It was concluded that the five‐arginine arrangement of the peptide performs selective recognition of the GNRA tetraloop and GNR(N)A pentaloop RNA structures, and that substitution of another functional amino acid residue at the 18th position in N‐peptide adds the recognition ability for a loop‐RNA sequence.
Long‐term safety and efficacy of second‐generation everolimus‐eluting stents compared to other limus‐eluting stents and bare metal stents in patients with acute coronary syndrome
Authors: Omar Alfazir , Torguson Rebecca , Kitabata Hironori , Pendyala Lakshmana K. , Loh Joshua P. , Magalhaes Marco A. , Satler Lowell F. , Suddath William O. , Pichard Augusto D. , Waksman Ron 
Published: March 2014

ObjectivesThis study aimed to investigate the long‐term safety and efficacy of everolimus‐eluting stents (EES) compared with other limus‐eluting stents and bare metal stents (BMS) in ACS patients.BackgroundThere have been concerns about the long‐term safety of drug‐eluting stents in the setting of acute coronary syndrome.MethodsThe study cohort included 1,612 patients presenting with acute coronary syndrome who underwent BMS, SES, E‐ZES, or EES implantation. End points included probable or definite stent thrombosis and major adverse cardiovascular events (MACE), defined as a composite of all‐cause death, Q‐wave myocardial infarction, and target lesion revascularization up to 3 years.ResultsThe overall MACE rates were significantly higher for both BMS and SES, but not E‐ZES, when compared with EES (EES vs. BMS: HR 2.68, 95% CI 1.91–3.78, P <0.001; EES vs. SES: HR 1.75, 95% CI 1.24–2.47, P = 0.001 and EES vs. E‐ZES: HR 1.08, 95% CI 0.65–1.77, P = 0.72). Stent thrombosis rates were similar for EES, E‐ZES, and BMS but higher for SES throughout the 3‐year follow‐up (EES vs. BMS: HR 1.02, 95% CI: 0.31–3.35, P = 0.973; EES vs. SES: HR 4.90, 95% CI: 1.75–13.69, P = 0.002 and EES vs. E‐ZES: HR 1.63, 95% CI 0.37–7.31, P = 0.449).ConclusionsThere was an improvement in the long‐term outcome for MACE with EES when compared to earlier‐generation stents, but this was comparable with the 2nd‐generation E‐ZES. There was no additional risk of early or late stent thrombosis in EES when compared with BMS. © 2014 Wiley Periodicals, Inc.