bluuebunny/crossref_metadata_2025_split huggingface dataset:
Casitas B Lineage Lymphoma b Is a Key Regulator of Peripheral Tolerance in Systemic Lupus Erythematosus
Authors: Gómez‐Martín Diana , Ibarra‐Sánchez María , Romo‐Tena Jorge , Cruz‐Ruíz José , Esparza‐López José , Galindo‐Campos Miguel , Díaz‐Zamudio Mariana , Alcocer‐Varela Jorge 
Published: December 2012

AbstractObjectiveTo analyze whether the expression and modulation of T cell receptor (TCR) signaling is dependent on Casitas B lineage lymphoma b (Cbl‐b) in T cells from patients with systemic lupus erythematosus (SLE) upon stimulation with a tolerogenic substance.MethodsPeripheral blood mononuclear cells were obtained from 20 patients with SLE (active disease or in remission) and 20 healthy controls. Levels of Cbl‐b expression were measured using reverse transcription–polymerase chain reaction and Western blotting in peripheral CD4+ T cells from SLE patients and healthy controls upon anergy induction. Cell proliferation was measured using the carboxyfluorescein diacetate succinimidyl ester dilution method. Cytokine production was analyzed by luminometry, and surface expression of activation markers was assessed by flow cytometry. Transfection assays were performed to induce overexpression of Cbl‐b, and phosphorylation of TCR‐associated kinases was evaluated.ResultsCD4+ T cells from SLE patients displayed resistance to anergy (as evidenced by increased cell proliferation, interleukin‐2 production, and expression of activation and costimulatory markers), and this was associated with altered Cbl‐b expression. Upon ionomycin treatment, primary T cells showed enhanced MAPK activity and decreased Akt phosphorylation, which was representative of the anergic state. In T cells from lupus patients, Cbl‐b overexpression led to increased expression of phosphorylated MAPK, thus indicating the reversibility of anergy resistance.ConclusionThese findings suggest that abnormal peripheral tolerance in SLE is caused by a deficiency in Cbl‐b, and that this ubiquitin ligase plays a key role in regulating TCR signaling during the induction of peripheral tolerance.
Copper(II) Complexes of 3,4,5‐Trisubstituted Pyrazolates: In Situ Formation of Pyrazole Rings from Different Carbon Centers
Authors: Das Oindrila , Malakar Tanmay , Mandal Arghya , Paul Ankan , Paine Tapan Kanti 
Published: December 2012

AbstractThe synthesis and characterization of two pyrazolate‐bridged dicopper(II) complexes, [Cu2(L1)2(H2O)2](ClO4)2 (1, HL1=3,5‐dipyridyl‐4‐(2‐keto‐pyridyl)pyrazole) and [Cu2(L2)2(H2O)2](ClO4)2 (2, HL2=3,5‐dipyridyl‐4‐benzoylpyrazole), are discussed. These copper(II) complexes are formed from the reactions between pyridine‐2‐aldehyde, 2‐acetylpyridine (for compound 1) or acetophenone (for compound 2), and hydrazine hydrate with copper(II) perchlorate hydrate under ambient conditions. The single‐crystal X‐ray structure of compound 1⋅2 H2O establishes the formation of a pyrazole ring from three different carbon centers through CC bond‐forming reactions, mediated by copper(II) ions. The free pyrazoles (HL1 and HL2) are isolated from their corresponding copper(II) complexes and are characterized by using various analytical and spectroscopic techniques. A mechanism for the pyrazole‐ring synthesis that proceeds through CC bond‐forming reactions is proposed and supported by theoretical calculations.
Pick‐up locations and bus allocation for transit‐based evacuation planning with demand uncertainty
Authors: Kulshrestha Ashish , Lou Yingyan , Yin Yafeng 
Published: December 2012

SUMMARYThis paper develops a decision‐support model for transit‐based evacuation planning under demand uncertainty. Demand uncertainty refers to the uncertainty associated with the number of transit‐dependent evacuees. A robust optimization model is proposed to determine the optimal pick‐up points for evacuees to assemble, and allocate available buses to transport the assembled evacuees between the pick‐up locations and different public shelters. The model is formulated as a mixed‐integer linear program and is solved via a cutting plane scheme. The numerical example based on the Sioux Falls network demonstrates that the robust plan yields lower total evacuation time and is reliable in serving the realized evacuee demand. Copyright © 2012 John Wiley & Sons, Ltd.
Non‐random mutation: The evolution of targeted hypermutation and hypomutation
Authors: Martincorena Iñigo , Luscombe Nicholas M. 
Published: December 2012

AbstractA widely accepted tenet of evolutionary biology is that spontaneous mutations occur randomly with regard to their fitness effect. However, since the mutation rate varies along a genome and this variation can be subject to selection, organisms might evolve lower mutation rates at loci where mutations are most deleterious or increased rates where mutations are most needed. In fact, mechanisms of targeted hypermutation are known in organisms ranging from bacteria to humans. Here we review the main forces driving the evolution of local mutation rates and identify the main limiting factors. Both targeted hyper‐ and hypomutation can evolve, although the former is restricted to loci under very frequent positive selection and the latter is severely limited by genetic drift. Nevertheless, we show how an association of repair with transcription or chromatin‐associated proteins could overcome the drift limit and lead to non‐random hypomutation along the genome in most organisms.Editor's suggested further reading in BioEssays Stress‐induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine Abstract
Aging modifies the enzymatic activities involved in 2‐arachidonoylglycerol metabolism
Authors: Pascual Ana C. , Gaveglio, Virginia L. , Giusto Norma M. , Pasquaré Susana J. 
Published: December 2012

AbstractOne of the principal monoacylglycerol (MAG) species in animal tissues is 2‐arachidonoylglycerol (2‐AG), and the diacylglycerol lipase (DAGL) pathway is the most important 2‐AG biosynthetic pathway proposed to date. Lysophosphatidate phosphatase (LPAase) activity is part of another 2‐AG‐forming pathway in which monoacylglycerol lipase (MAGL) is the major degrading enzyme. The purpose of this study was to analyze the manner in which DAGL, LPAase, and MAGL enzymes are modified in the central nervous system (CNS) during aging. To this end, diacylglycerols (DAGs) and MAGs of different composition were used as substrates of DAGL and MAGL, respectively. All enzymatic activities were evaluated in membrane and soluble fractions as well as in synaptic terminals from the cerebral cortex (CC) of adult and aged rats. Results related to 2‐AG metabolism show that aging: (a) decreases DAGL‐α expression in the membrane fraction whereas in synaptosomes it increases DAGL‐β and decreases MAGL expression; (b) decreases LPAase activity in both membrane and soluble fractions; (c) decreases DAGL and stimulates LPAase activities in CC synaptic terminals; (d) stimulates membrane‐associated MAGL‐coupled DAGL activity; and (e) stimulates MAGL activity in CC synaptosomes. Our results also reveal that during aging the net balance between the enzymatic activities involved in 2‐AG synthesis and breakdown is low availability of 2‐AG in CC membrane fractions and synaptic terminals. Taken together, our results lead us to conclude that these enzymes play crucial roles in the regulation of 2‐AG tissue levels during aging. © 2012 BioFactors, 2013
Curcumin in inflammatory diseases
Authors: Shehzad Adeeb , Rehman Gauhar , Lee Young Sup 
Published: December 2012

AbstractCurcumin (diferuloylmethane), a yellow coloring agent extracted from turmeric is also used as a remedy for the treatment and prevention of inflammatory diseases. Acute and chronic inflammation is a major factor in the progression of obesity, type II diabetes, arthritis, pancreatitis, cardiovascular, neurodegenerative and metabolic diseases, as well as certain types of cancer. Turmeric has a long history of use in Ayurvedic medicine for the treatment of inflammatory disorders. Recent studies on the efficacy and therapeutic applicability of turmeric have suggested that the active ingredient of tumeric is curcumin. Further, compelling evidence has shown that curcumin has the ability to inhibit inflammatory cell proliferation, invasion, and angiogenesis through multiple molecular targets and mechanisms of action. Curcumin is safe, non‐toxic, and mediates its anti‐inflammatory effects through the down‐regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes that all promote inflammation. In addition, curcumin induces apoptosis through mitochondrial and receptor‐mediated pathways, as well as activation of caspase cascades. In the current study, the anti‐inflammatory effects of curcumin were evaluated relative to various chronic inflammatory diseases. Based on the available pharmacological data obtained from in vitro and in vivo research, as well as clinical trials, an opportunity exists to translate curcumin into clinics for the prevention of inflammatory diseases in the near future. © 2012 BioFactors, 39(1):69–77, 2013
Luminal accumulation of newly synthesized morphine‐3‐glucuronide in rat liver microsomal vesicles
Authors: Révész Katalin , Tóth Blanka , Staines Adam G. , Coughtrie Michael W. H. , Mandl József , Csala Miklós 
Published: December 2012

AbstractMorphine is converted to morphine 3‐β‐D‐glucuronide (M3G) by the UDP‐glucuronosyltransferase Ugt2b1 in the endoplasmic reticulum (ER) of rat liver. Because of its luminal localization, UGT activity requires UDP‐glucuronate import and glucuronide export across the ER membrane. The former transport is generally considered to be rate limiting and to explain the latency of UGT activities in intact microsomal vesicles. However, some observations indicate that the release of bulky glucuronides, such as M3G, might also be rate limiting for glucuronidation. This assumption was tested by characterizing the transport of M3G and its distribution between the intra‐ and extravesicular spaces during synthesis in rat liver microsomes. The amount of vesicle‐associated M3G was measured using rapid filtration and LC‐MS measurement. Our results reveal a remarkable accumulation of newly synthesized M3G in the microsomal lumen above the equilibrium. The transport showed a linear concentration‐dependence in a wide range (5–200 μM). Therefore, the build‐up of high (about 20 μM) luminal M3G concentration could adjust the rate of release to that of synthesis (44.85 ± 4.08 pmol/min/mg protein) during the conjugation of 100 μM morphine. These data can explain earlier findings indicative of separate intracellular pools of M3G in rat liver. Accumulation of bulky glucuronides in the ER lumen might also play an important role in their targeting and in the control of biliary excretion. © 2012 BioFactors, 2013
Flow Chemistry Syntheses of Styrenes, Unsymmetrical Stilbenes and Branched Aldehydes
Authors: Bourne Samuel L. , O'Brien Matthew , Kasinathan Sivarajan , Koos Peter , Tolstoy Päivi , Hu Dennis X. , Bates Roderick W. , Martin Benjamin , Schenkel Berthold , Ley Steven V. 
Published: December 2012

AbstractTwo tandem flow chemistry processes have been developed. A single palladium‐catalysed Heck reaction with ethylene gas provides an efficient synthesis for functionalised styrenes. Through further elaboration the catalyst becomes multi‐functional and performs a second Heck reaction providing a single continuous process for the synthesis of unsymmetrical stilbenes. In addition, the continuous, rhodium‐catalysed, hydroformylation of styrene derivatives with syngas affords branched aldehydes with good selectivity. Incorporation of an in‐line aqueous wash and liquid–liquid separation allowed for the ethylene Heck reaction to be telescoped into the hydroformylation step such that a single flow synthesis of branched aldehydes directly from aryl iodides was achieved. The tube‐in‐tube semi‐permeable membrane‐based gas reactor and liquid–liquid separator both play an essential role in enabling these telescoped flow processes.
A Pilot‐Scale System for Carbon Molecular Sieve Hollow Fiber Membrane Manufacturing
Authors: Karvan O. , Johnson J. R. , Williams P. J. , Koros W. J. 
Published: December 2012

AbstractCarbon molecular sieve (CMS) membranes offer advantages over traditional polymeric membrane materials, but scale‐up of manufacturing systems has not received much attention. In the recent decade, there has been a dramatic increase in fundamental research on these materials with a variety of applications being studied. The results from a pilot‐scale CMS production system are presented. This system was designed based on extensive laboratory research, and hollow fiber membranes produced in this system show similar performance compared to membranes produced using a smaller bench‐scale system. After optimizing the system design, a 93 % recovery of the precursor fibers for use in membrane module preparation were obtained.
Ruthenium Complexes with Hydrophobic Ligands That Are Key Factors for the Optical Imaging of Physiological Hypoxia
Authors: Komatsu Hirokazu , Yoshihara Kazuki , Yamada Hisatsugu , Kimura Yu , Son Aoi , Nishimoto Sei‐ichi , Tanabe Kazuhito 
Published: December 2012

AbstractThe phosphorescence emission of ruthenium complexes was applied to the optical imaging of physiological hypoxia. We prepared three complexes with hydrophobic substituents on the phenanthroline ligand and characterized their emission, which was quenched by molecular oxygen. Among the complexes synthesized in this study, a pyrene chromophore‐linked ruthenium complex, Ru‐Py, exhibited optimal properties for the imaging of hypoxia; the prolonged lifetime of the triplet excited state of the ruthenium chromophore, which was induced by efficient energy distribution and transfer from the pyrene unit, provided the highest sensitivity towards molecular oxygen. The introduction of hydrophobic pyrene increased the lipophilicity of the complex, leading to enhanced cellular uptake. Consequently, the bright phosphorescence of Ru‐Py was seen in the cytoplasm of viable hypoxic cells, whereas the signal from aerobic cells was markedly weaker. Thus, we could clearly discriminate between hypoxic and aerobic cells by monitoring the phosphorescence emission. Furthermore, Ru‐Py was applied to optical imaging in live mice. An intramuscular injection of Ru‐Py successfully visualized ischemia‐based hypoxia, which was constructed by leg banding.
Preoperative BRAF(V600E) mutation screening is unlikely to alter initial surgical treatment of patients with indeterminate thyroid nodules
Authors: Kleiman David A. , Sporn Matthew J. , Beninato Toni , Crowley Michael J. , Nguyen Anvy , Uccelli Alessia , Scognamiglio Theresa , Zarnegar Rasa , Fahey Thomas J. 
Published: December 2012

AbstractBACKGROUND:Preoperative B‐type Raf kinase Val600Glu mutation, or BRAF(V600E), analysis has been proposed as a tool to guide initial surgery for indeterminate thyroid nodules. This study sought to determine if cytologic markers of malignancy are associated with the BRAF(V600E) mutation and if preoperative BRAF(V600E) testing would alter the initial management of patients with indeterminate nodules.METHODS:Patients who underwent surgery for a thyroid nodule between 2003 and 2012 at a tertiary care center were prospectively enrolled. Stored nodule samples were retrospectively genotyped for the BRAF(V600E) mutation. BRAF(V600E) status, demographics, cytologic and histopathologic findings, and choice of initial surgery were examined.RESULTS:A total of 960 patients were enrolled, of which 310 (32%) had an indeterminate nodule. The BRAF(V600E) mutation was identified in 13 patients (4%), 12 of whom had either cytologic atypia or were Bethesda category V. Three percent of Bethesda category III or IV nodules that were malignant harbored the mutation compared with 42% of Bethesda category V malignancies. Nuclear grooves (P = .030), pseudoinclusions (P < .001), and oval nuclei (P = .022) were all more common among BRAF(V600E) mutants. The sensitivities of using BRAF testing alone, cytologic atypia/Bethesda category V classification, or both, were 15%, 73%, and 76%, respectively. Twelve of the 13 BRAF(V600E) mutants had total thyroidectomies initially due to worrisome cytologic features, and therefore the initial management of only one patient would have been altered if BRAF(V600E) testing had been performed preoperatively.CONCLUSIONS:Preoperative mutation screening for BRAF(V600E) does not meaningfully improve risk stratification and is unlikely to alter the initial management of patients with indeterminate nodules. Cancer 2013. © 2012 American Cancer Society.
Inhibition of farnesoid X receptor controls esophageal cancer cell growth in vitro and in nude mouse xenografts
Authors: Guan Baoxiang , Li Hao , Yang Zhengduo , Hoque Ashraful , Xu Xiaochun 
Published: December 2012

AbstractBACKGROUND:Gastroesophageal reflux is a risk factor for esophageal adenocarcinoma, and bile acid and its farnesoid X receptor (FXR) have been implicated in esophageal tumorigenesis. The authors investigated the role of FXR expression and activity in esophageal cancer initiation and growth.METHODS:FXR expression in esophageal adenocarcinoma tissues was assessed by immunohistochemistry. Knockdown of FXR expression in esophageal cancer cells in vitro and in nude mice xenografts was suppressed by FXR small hairpin RNA (shRNA) and guggulsterone (a natural FXR inhibitor). Esophageal cancer cells were treated with bile acids to demonstrate their effects on growth‐promoting genes.RESULTS:FXR was expressed in 48 of 59 esophageal adenocarcinoma tissues (81.3%), and this overexpression was associated with higher tumor grade, larger tumor size, and lymph node metastasis; however, was inversely associated with retinoic acid receptor‐β2 (RAR‐β2) expression. Knockdown of FXR expression suppressed tumor cell growth in vitro and in nude mouse xenografts. Guggulsterone reduced the viability of esophageal cancer cells in a time‐dependent and dose‐dependent manner, whereas this effect was diminished after knockdown of FXR expression. Guggulsterone induced apoptosis through activation of caspase‐8, caspase‐9, and caspase‐3 in tumor cells. FXR mediated bile acid‐induced alterations of gene expression, eg, RAR‐β2 and cyclooxygenase‐2 (COX‐2).CONCLUSIONS:Inhibition of FXR by FXR shRNA or guggulsterone suppressed tumor cell viability and induced apoptosis in vitro, and it reduced tumor formation and growth in nude mouse xenografts. FXR also mediated bile acid‐induced alterations of cell growth‐related genes in esophageal cancer cells. Cancer 2013. © 2012 American Cancer Society.
Feasibility and safety of sequential research‐related tumor core biopsies in clinical trials
Authors: Lee Jung‐min , Hays John L. , Noonan Anne M. , Squires Jennifer , Minasian Lori , Annunziata Christina , Wood Bradford J. , Yu Minshu , Calvo Katherine R. , Houston Nicole , Azad Nilofer , Kohn Elise C. 
Published: December 2012

AbstractBACKGROUND:There has been increasing interest in serial research biopsies in studies of targeted therapies. Definition of patient characteristics and optimal target tissue for safe research tumor biopsy in the era of antiangiogenic and targeted agents is needed.METHODS:This institutional review board‐approved, retrospective study included chart and interventional radiology case review from 6 phase 1/2 studies at the National Cancer Institute.RESULTS:One hundred forty‐two of 150 protocol patients who were approached gave consent for research biopsies. Patients' median age was 56 years (range, 27‐78 years), their median body mass index was 25.8 kg/m2 (range, 14.4‐46.2 kg/m2), they had an Eastern Cooperative Oncology Group performance status of 0 or 1, and they had normal end‐organ function. Baseline biopsies were collected from 138 of 142 patients (97%), and paired specimens were collected from 96 (70%). Most patients had metastatic gynecologic cancers (85%), and 78% had target disease below the diaphragm with a median size of 2.7 cm (range, 1‐14.5 cm). Protocol therapies included kinase inhibitors (35%), angiogenesis inhibitors (54%), and olaparib/carboplatin (11%); therapy was not interrupted for biopsies. All adverse events were uncomplicated and were observed in 4 patients (liver subcapsular hematoma in 1 patient, vasovagal syncope in 2 patients, and pneumothorax in 1 patient). The complication rate in obese patients was similar to that in nonobese patients (3 of 108 patients vs 1 of 34 patients, respectively). Sixty‐seven patients (48%) were receiving bevacizumab at the time of subsequent biopsies. The complication rate was not different between patients who were and were not receiving bevacizumab (3 of 67 patients vs 1 of 71 patients, respectively). Ninety‐five percent of biopsies yielded useable material.CONCLUSIONS:Serial percutaneous core‐needle biopsies can be obtained safely and yield material applicable for multiple translational applications. Obesity and/or concomitant antiangiogenic therapy and depth of disease did not increase the risk or preclude the successful acquisition of useful tissue. Cancer 2013. © 2012 American Cancer Society.
Antioxidant intake and pancreatic cancer risk
Authors: Han Xuesong , Li Jingjing , Brasky Theodore M. , Xun Pengcheng , Stevens June , White Emily , Gammon Marilie D. , He Ka 
Published: December 2012

AbstractBACKGROUND:Oxidative stress causes damage to many components of human cells (ie, proteins, lipids, and DNA) and is involved in carcinogenesis. Nutrients with antioxidant properties may protect against oxidative stress. In this study, the authors examined the intake of antioxidants from diet and supplements in relation to pancreatic cancer risk among participants of the Vitamins and Lifestyle (VITAL) Study.METHODS:The participants included 77,446 men and women ages 50 to 76 years who were residents of western Washington State and who completed a baseline questionnaire between 2000 and 2002. Participants reported usual diet over the past year and use of supplements over the past 10 years in addition to demographic and lifestyle factors. During a median follow‐up of 7.1 years, 184 participants developed pancreatic adenocarcinoma. Cox proportional hazards models were used to estimate multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for 7 antioxidants: β‐carotene, lutein plus zeaxanthin, lycopene, vitamin C, vitamin E, selenium, and zinc.RESULTS:An inverse association was observed between dietary selenium and the risk of pancreatic cancer (medium vs low intake: HR, 0.58; 95% CI, 0.35‐0.94; high vs low intake: HR, 0.44; 95% CI, 0.23‐0.85; Ptrend = .01); however, when supplemental and dietary exposures were combined, the association was no longer statistically significant.CONCLUSIONS:Dietary selenium intake was inversely associated with the risk of pancreatic cancer, and the observed association was attenuated by selenium supplementation. Cancer 2013. © 2012 American Cancer Society.