tbuckley/cabot-search huggingface dataset:
Brief Report: Association of <i>CCR1</i>, <i>KLRC4</i>, <i>IL12A–AS1</i>, <i>STAT4</i>, and <i>ERAP1</i> With Behçet's Disease in Iranians
Authors: Inês Sousa, Farhad Shahram, David Francisco, Fereydoun Davatchi, Bahar Sadeghi Abdollahi, Fahmida Ghaderibarmi, Abdolhadi Nadji, Niloofar Mojarad Shafiee, Joana M. Xavier, Sofia A. Oliveira
Journal: Arthritis & Rheumatology (2015)

To independently replicate the top findings from 4 published genome-wide association studies (GWAS) of susceptibility genes in Behçet's disease (BD).We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R-IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers.Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A-AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 × 10(-9) ≤ Pallele ≤ 7.55 × 10(-3) ) and sex-adjusted genotypic association tests (6.01 × 10(-9) ≤ adjusted P value ≤ 1.30 × 10(-2) ). For all 6 SNPs tested by meta-analysis (Pmeta ), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] for A allele 1.29 [95% confidence interval (95% CI) 1.21-1.37], Pmeta = 2.34 × 10(-16) ; for rs7616215, OR for C allele 0.70 [95% CI 0.65-0.76], Pmeta = 1.54 × 10(-19) ; for rs17810546, OR for A allele 0.60 [95% CI 0.52-0.70], Pmeta = 6.34 × 10(-11) ; for rs2617170, OR for T allele 0.76 [95% CI 0.70-0.81], Pmeta = 2.75 × 10(-14) ; for rs13154629, OR for TT genotype 2.76 [95% CI 2.01-3.80], Pmeta = 3.57 × 10(-10) ).This study reinforces the notion that CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R-IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD.
THE MAMMALIAN LOW-DENSITY LIPOPROTEIN RECEPTOR FAMILY
Authors: M. Mahmood Hussain, Dudley K. Strickland, Ahmed Bakillah
Journal: Annual Review of Nutrition (1999)

The low-density lipoprotein (LDL) receptor (LDL-R) family consists of cell-surface receptors that recognize extracellular ligands and internalize them for degradation by lysosomes. The LDL-R is the prototype of this family, which also contains very-low-density lipoprotein receptors (VLDL-R), apolipoprotein E receptor 2, LRP, and megalin. The family members contain four major structural modules: the cysteine-rich complement-type repeats, epidermal growth factor precursor-like repeats, a transmembrane domain, and a cytoplasmic domain. Each structural module serves distinct and important functions. These receptors bind several structurally dissimilar ligands. It is proposed that instead of a primary sequence, positive electrostatic potential in different ligands constitutes a receptor binding domain. This family of receptors plays crucial roles in various physiologic functions. LDL-R plays an important role in cholesterol homeostasis. Mutations cause familial hypercholesterolemia and premature coronary artery disease. LDL-R-related protein plays an important role in the clearance of plasma-activated alpha 2-macroglobulin and apolipoprotein E-enriched lipoproteins. It is essential for fetal development and has been associated with Alzheimer's disease. Megalin is the major receptor in absorptive epithelial cells of the proximal tubules and an antigenic determinant for Heymann nephritis in rats. Mutations in a chicken homolog of VLDL-R cause female sterility and premature atherosclerosis. This receptor is not expressed in liver tissue; however, transgenic expression of VLDL-R in liver corrects hypercholesterolemia in experiment animals, which suggests that it can be a candidate for gene therapy for various hyperlipidemias. The functional importance of individual receptors may lie in their differential tissue expression. The regulation of expression of these receptors occurs at the transcriptional level. Expression of the LDL-R is regulated by intracellular sterol levels involving novel membrane-bound transcription factors. Other members of the family are not regulated by sterols. All the members are, however, regulated by hormones and growth factors, but the mechanisms of regulation by hormones have not been elucidated. Studies of these receptors have provided important insights into receptor structure-function and mechanisms of ligand removal and catabolism. It is anticipated that increased knowledge about the LDL-R family members will open new avenues for the treatment of many disorders.
P143 NF-kappa B (NF- B) and activator protein-1 (AP-1) DNA binding in the quadriceps of COPD patients
Authors: S. A. Natanek, R. C. J. Langen, H. R. Gosker, G. S. Marsh, I. Slot, N. S. Hopkinson, W. D.-C. Man, P. R. Kemp, J. Moxham, A. M. W. J. Schols, M. I. Polkey
Journal: Thorax (2010)

<h3>Introduction</h3> Animal work implicates NF-κB and AP-1 activation in muscle atrophy (Cai <i>et al, 2004 and</i> Costelli <i>et al</i>, 2005). Prior study of seven COPD patients with a low BMI and seven COPD patients with a normal BMI suggested that NF-κB DNA binding was increased in the former (Agusti <i>et al</i>, 2004) although others have not demonstrated NF-κB activation in COPD muscle (Plant <i>et al</i>, 2009). <h3>Aim</h3> Evaluate NF-κB and AP-1 activation in the quadriceps of patients with stable COPD in relation to muscle atrophy. <h3>Methods</h3> 114 COPD patients and 30 healthy age-matched controls underwent measurements of lung function and bioelectrical impedance to determine fat-free mass index (FFMI) and a percutaneous Bergstrom needle biopsy of the quadriceps. Transcription factor ELISAs were performed on nuclear extracts from quadriceps muscle to measure quantities of NF-κB P50, P65, and AP-1 c-jun subunits in muscle nuclei capable of binding DNA. Immunohistochemistry was used to determine type I and II fibre cross-sectional area (CSA) from muscle sections. <h3>Results</h3> There was no evidence of increased quantities of muscle nuclear P65 or P50 binding DNA in patients compared with controls and the quantity of muscle nuclear AP-1 c-jun binding DNA was lower in patients than controls (336 (174,513)RLU vs 508 (284,846)RLU, p=0.01). Patients with low FFMI (≤15 and 16 kg/m<sup>2</sup> for females and males respectively, n=54) did not have increased quantities of P65, P50 or c-jun binding DNA compared with patients with normal FFMI (n=60, (286 (171,407) vs 260 (176,376) RLU p=0.94, 880 (400,1373) vs 1064 (654,1586) RLU p=0.33 and 313 (155,484) vs 353 (181,570) RLU p=0.42 respectively). There were no correlations between quantities of the transcription factors binding DNA and quadriceps type I or II fibre CSA or type I, IIa or IIx fibre proportions. <h3>Conclusion</h3> NF-κB and AP-1 DNA-binding were not increased in the quadriceps of patients with stable COPD compared to controls and did not predict reduced FFMI or quadriceps fibre size, nor quadriceps fibre proportions, in patients.
Blood and Urinary Changes in Patients with Ileostomies and Ileorectal Anastomoses
Authors: A. M. Singer, R. C. Bennett, N. G. Carter, E. S. R. Hughes
Journal: BMJ (1973)

Biochemical investigations done on the blood and urine of currently healthy, uncomplicated patients previously treated by either proctocolectomy and ileostomy or colectomy and ileorectal anastomosis for ulcerative colitis were compared with estimations on matched controls. The most striking finding was the reduced urine volume, and to a lesser extent its sodium content, in patients with ileostomies. The urinary pH indicated persistent acidity in postoperative patients but this was also a remarkably constant feature in control subjects. These findings are in agreement with other studies related to the occurrence of urinary calculi after colectomy and ileostomy, and are consistent with the contention that there is a lower incidence of calculi after ileorectal anastomosis.
Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study
Authors: F van Leth, P Phanuphak, K Ruxrungtham, E Baraldi, S Miller, B Gazzard, P Cahn, UG Lalloo, IP van der Westhuizen, DR Malan, MA Johnson, BR Santos, F Mulcahy, R Wood, GC Levi, G Reboredo, K Squires, I Cassetti, D Petit, F Raffi, C Katlama, RL Murphy, A Horban, JP Dam, E Hassink, R van Leeuwen, P Robinson, FW Wit, JMA Lange
Journal: The Lancet (2004)
Characterization of human high molecular weight kininogen. Procoagulant activity associated with the light chain of kinin-free high molecular weight kininogen.
Authors: R E Thompson, R Mandle, A P Kaplan
Journal: The Journal of Experimental Medicine (1978)

Human high molecular weight (HMW) kininogen has been isolated and was found to be a single chain protein of approximately equal to 120,000 daltons. Upon digestion with plasma kallikrein bradykinin is generated, and SDS gel electrophoresis of the kinin-free protein reveals an apparent loss in size of 15,000 daltons. The kinin-free kininogen retains full activity as a coagulation factor and consists of two chains: a heavy chain of approximately equal to 66,000 daltons disulfide-linked to a light chain of 37,000 daltons. The heavy chain of HMW kininogen shares antigenic determinants with LMW kininogen and possesses no detectable coagulant activity. The isolated light chain is shown to be responsible for the coagulant activity of HMW kininogen and contains a unique antigenic determinant that distinguishes HMW kininogen from low molecular weight kininogen.
Regulation of the Epigenome by Vitamin C
Authors: Juan I. Young, Stephan Züchner, Gaofeng Wang
Journal: Annual Review of Nutrition (2015)

Emerging evidence suggests that ascorbate, the dominant form of vitamin C under physiological pH conditions, influences activity of the genome via regulating epigenomic processes. Ascorbate serves as a cofactor for Ten-eleven translocation (TET) dioxygenases that catalyze the oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), and further to 5-formylcytosine (5fC) and to 5-carboxylcytosine (5caC), which are ultimately replaced by unmodified cytosine. The Jumonji C (JmjC)-domain-containing histone demethylases also require ascorbate as a cofactor for histone demethylation. Thus, by primarily participating in the demethylation of both DNA and histones, ascorbate appears to be a mediator of the interface between the genome and environment. Furthermore, redox status has a profound impact on the bioavailability of ascorbate in the nucleus. In order to bridge the gap between redox biology and genomics, we suggest an interdisciplinary research field that can be termed redox genomics to study dynamic redox processes in health and diseases. This review examines the evidence and potential molecular mechanism of ascorbate in the demethylation of the genome, and it highlights potential epigenetic roles of ascorbate in various diseases.
Ethnic Disparities in Unmet Need for Alcoholism, Drug Abuse, and Mental Health Care
Authors: Kenneth Wells, Ruth Klap, Alan Koike, Cathy Sherbourne
Journal: American Journal of Psychiatry (2001)

Recent policy has focused on documenting and reducing ethnic disparities in availability and quality of health care. The authors examined differences by ethnic status in unmet need for alcoholism, drug abuse, and mental health treatment.Data were from a follow-up survey of adult respondents to a 1996-1997 national survey. Non-Hispanic whites, African Americans, and Hispanics were compared in access to alcoholism and drug abuse treatment and mental health care (primary or specialty), unmet need for care, satisfaction with care, and use of active treatment for alcoholism, drug abuse, and mental health problems in the prior 12 months.A total of 31.9% of whites, 28.1% of African Americans, and 30.1% of Hispanics had some alcoholism, drug abuse, and mental health care, mostly in primary care. Among those with perceived need, compared to whites, African Americans were more likely to have no access to alcoholism, drug abuse, or mental health care (25.4% versus 12.5%), and Hispanics were more likely to have less care than needed or delayed care (22.7% versus 10.7%). Among those with need, whites were more likely than Hispanics or African Americans to be receiving active alcoholism, drug abuse, or mental health treatment (37.6% versus 22.4%-25.0%).The authors document greater unmet need for alcoholism and drug abuse treatment and mental health care among African American and Hispanics relative to whites. New policies are needed to improve access to and quality of alcoholism, drug abuse, and mental health treatment across diverse populations.
Severe impaired respiratory ciliary function in Wegener granulomatosis
Authors: S Ullrich, H Gustke, P Lamprecht, W L Gross, U Schumacher, P Ambrosch, M Laudien
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> The pathogenesis of granulomatous inflammation in the respiratory tract and autoimmunity in Wegener granulomatosis (WG) are poorly understood. Since mucociliar clearance represents the first major line of defence in the respiratory tract and its breakdown facilitates chronic inflammation, we investigated ciliary beat frequency (CBF) in WG. <h3>Methods:</h3> Nasal epithelial cells were obtained from 30 patients with WG with involvement of the upper respiratory tract, 12 patients with other inflammatory rheumatic disease and 10 healthy controls. CBF was measured at 5 and 24 h after collection. Results were correlated with clinical data. <h3>Results:</h3> CBF was significantly reduced in WG compared to disease and healthy controls after 5 and 24 h. In WG, CBF almost stagnated after 24 h. Reduction of CBF correlated with the cumulative number of immunosuppressive agents in WG, but not in disease controls. No correlation was found between CBF impairment and cyclophosphamide levels, disease extent, disease activity, disease duration, serological and microbiological findings, or inflammation markers. <h3>Conclusion:</h3> CBF is severely impaired in WG, potentially influenced by immunosuppressive treatment. To what extent CBF impairment and subsequent barrier dysfunction are caused by other factors still has to be elucidated. Supportive measures to improve mucociliary clearance should be discussed in patients with WG.
A Phase I Trial of a Potent P-Glycoprotein Inhibitor, Zosuquidar Trihydrochloride (LY335979), Administered Intravenously in Combination with Doxorubicin in Patients with Advanced Malignancy
Authors: Alan Sandler, Michael Gordon, Dinesh P. de Alwis, Isabelle Pouliquen, Lisa Green, Phil Marder, Ajai Chaudhary, Karen Fife, Linda Battiato, Christopher Sweeney, Christopher Jordan, Michael Burgess, Christopher A. Slapak
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Our intention was to (a) to investigate the safety and tolerability of a potent P-glycoprotein modulator, zosuquidar trihydrochloride (LY335979), when administered i.v. alone or in combination with doxorubicin, (b) to determine the pharmacokinetics of zosuquidar and correlate exposure to inhibition of P-glycoprotein function in a surrogate assay, and (c) to compare the pharmacokinetics of doxorubicin in the presence and absence of zosuquidar. Patients and Methods: Patients with advanced malignancies who provided written informed consent received zosuquidar and doxorubicin administered separately during the first cycle of therapy and then concurrently in subsequent cycles. Zosuquidar was given i.v. over 48 h in a cohort-dose escalation manner until the occurrence of dose-limiting toxicity or protocol specified maximum exposure. Doxorubicin doses of 45, 60, 75 mg/m2 were administered during the course of the trial. Results: Dose escalation proceeded through 9 cohorts with a total of 40 patients. The maximal doses administered were 640 mg/m2 of zosuquidar and 75 mg/m2 of doxorubicin. No dose-limiting toxicity of zosuquidar was observed. Pharmacokinetic analysis revealed that, in the presence of zosuquidar at doses that exceeded 500 mg, there was a modest decrease in clearance (17–22%) and modest increase in area under the curve (15–25%) of doxorubicin. This change was associated with an enhanced leukopenia and thrombocytopenia but was without demonstrable clinical significance. The higher doses of zosuquidar were associated with maximal P-glycoprotein inhibition in natural killer cells. Conclusion: Zosuquidar can be safely coadministered with doxorubicin using a 48 h i.v. dosing schedule.
Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia
Authors: A. Österborg, R. Foà, R. F. Bezares, C. Dearden, M. J S Dyer, C. Geisler, T. S. Lin, M. Montillo, M. H J van Oers, C. M. Wendtner, K. R. Rai
Journal: Leukemia (2009)
Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration.
Authors: C Weyer, P A Tataranni, R E Pratley
Journal: Diabetes Care (2000)

An elevated C3 concentration has been reported in people with obesity, type 2 diabetes, hypertension, and dyslipidemia, and has been proposed to play a role in the development of atherosclerosis. We hypothesized that an elevated C3 concentration might be linked to insulin resistance and/or hyperinsulinemia, abnormalities commonly observed in association with the above conditions.Fasting concentrations of C3 and acylation stimulating protein (ASP, C3adesarg), a cleavage product of C3 recently found to stimulate glucose uptake in vitro, were measured in 33 healthy nondiabetic Pima Indians (14 women and 19 men; age 27 +/- 1 and body fat 33 +/- 1%, means +/- SEM). Subjects were characterized for body composition dual-energy X-ray absorptiometry, insulin action (insulin-stimulated glucose disposal [M], hyperinsulinemic glucose clamp), and glucose tolerance (75-g oral glucose tolerance test).Fasting C3 and ASP concentrations were positively correlated (r = 0.43, P < 0.05). Fasting C3 concentration was closely related to percent body fat (r = 0.77), M (r = -0.75), and fasting insulin concentration (r = 0.72) (all P < 0.0001). Fasting C3 concentrations remained significantly related to M and fasting insulin after adjusting for percent body fat (partial r = -0.53 and 0.33, both P < 0.05). In subjects with impaired glucose tolerance, fasting C3 concentrations were higher than in those with normal glucose tolerance--a difference that remained after adjustment for percent body fat and M. We found that fasting ASP concentrations were significantly related to percent body fat (r = 0.37, P < 0.05), but not to M or fasting insulin.In Pima Indians, fasting C3 concentration is closely related to adiposity, insulin action, and fasting insulin levels and may thus be a mediator for the postulated link between obesity, insulin resistance, hyperinsulinemia, and possibly atherosclerosis.
A Phase 3, Randomised, Double-Blind, Placebo-Controlled, International Study of MEDI4736 in Patients with Locally Advanced, Unresectable NSCLC (Stage III) Who have not Progressed following Platinum-Based, Concurrent Chemoradiation Therapy (Pacific)
Authors: S. Antonia, N.O. Iannotti, M.A. Salamat, A.D. Krebs, D. Jayawardene, M. Ballas, P.K. Stockman
Journal: Annals of Oncology (2014)
ARTEMIS Nuclease Facilitates Apoptotic Chromatin Cleavage
Authors: Sébastien Britton, Philippe Frit, Denis Biard, Bernard Salles, Patrick Calsou
Journal: Cancer Research (2009)

One hallmark of apoptosis is DNA degradation that first appears as high molecular weight fragments followed by extensive internucleosomal fragmentation. During apoptosis, the DNA-dependent protein kinase (DNA-PK) is activated. DNA-PK is involved in the repair of DNA double-strand breaks (DSB) and its catalytic subunit is associated with the nuclease ARTEMIS. Here, we report that, on initiation of apoptosis in human cells by agents causing DNA DSB or by staurosporine or other agents, ARTEMIS binds to apoptotic chromatin together with DNA-PK and other DSB repair proteins. ARTEMIS recruitment to chromatin showed a time and dose dependency. It required DNA-PK protein kinase activity and was blocked by antagonizing the onset of apoptosis with a pan-caspase inhibitor or on overexpression of the antiapoptotic BCL2 protein. In the absence of ARTEMIS, no defect in caspase-3, poly(ADP-ribose) polymerase-1, and XRCC4 cleavage or in H2AX phosphorylation was observed and DNA-PK catalytic subunit was still phosphorylated on S2056 in response to staurosporine. However, DNA fragmentation including high molecular weight fragmentation was delayed in ARTEMIS-deficient cells compared with cells expressing ARTEMIS. In addition, ARTEMIS enhanced the kinetics of MLL gene cleavage at a breakage cluster breakpoint that is frequently translocated in acute or therapy-related leukemias. These results show a facilitating role for ARTEMIS at least in early, site-specific chromosome breakage during apoptosis.
Nanoparticle clearance is governed by Th1/Th2 immunity and strain background
Authors: Stephen W. Jones, Reid A. Roberts, Gregory R. Robbins, Jillian L. Perry, Marc P. Kai, Kai Chen, Tao Bo, Mary E. Napier, Jenny P.Y. Ting, Joseph M. DeSimone, James E. Bear
Journal: Journal of Clinical Investigation (2013)

Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopy-based assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte-derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans.