tbuckley/cabot-search huggingface dataset:
Gene‐Based Meta‐Analysis of Genome‐Wide Association Study Data Identifies Independent Single‐Nucleotide Polymorphisms in <i>ANXA6</i> as Being Associated With Systemic Lupus Erythematosus in Asian Populations
Authors: Jing Zhang, Lu Zhang, Yan Zhang, Jing Yang, Mengbiao Guo, Liangdan Sun, Hai‐Feng Pan, Nattiya Hirankarn, Dingge Ying, Shuai Zeng, Tsz Leung Lee, Chak Sing Lau, Tak Mao Chan, Alexander Moon Ho Leung, Chi Chiu Mok, Sik Nin Wong, Ka Wing Lee, Marco Hok Kung Ho, Pamela Pui Wah Lee, Brian Hon‐Yin Chung, Chun Yin Chong, Raymond Woon Sing Wong, Mo Yin Mok, Wilfred Hing Sang Wong, Kwok Lung Tong, Niko Kei Chiu Tse, Xiang‐Pei Li, Yingyos Avihingsanon, Pornpimol Rianthavorn, Thavatchai Deekajorndej, Kanya Suphapeetiporn, Vorasuk Shotelersuk, Shirley King Yee Ying, Samuel Ka Shun Fung, Wai Ming Lai, Maria‐Mercè Garcia‐Barceló, Stacey S. Cherny, Pak Chung Sham, Yong Cui, Sen Yang, Dong Qing Ye, Xue‐Jun Zhang, Yu Lung Lau, Wanling Yang
Journal: Arthritis & Rheumatology (2015)

Previous genome-wide association studies (GWAS), which were mainly based on single-variant analysis, have identified many systemic lupus erythematosus (SLE) susceptibility loci. However, the genetic architecture of this complex disease is far from being understood. The aim of this study was to investigate whether using a gene-based analysis may help to identify novel loci, by considering global evidence of association from a gene or a genomic region rather than focusing on evidence for individual variants. Based on the results of a meta-analysis of 2 GWAS of SLE conducted in 2 Asian cohorts, we performed an in-depth gene-based analysis followed by replication in a total of 4,626 patients and 7,466 control subjects of Asian ancestry. Differential allelic expression was measured by pyrosequencing. More than one-half of the reported SLE susceptibility loci showed evidence of independent effects, and this finding is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel SLE susceptibility gene, with several single-nucleotide polymorphisms (SNPs) contributing independently to the association with disease. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in peripheral blood mononuclear cells from heterozygous healthy control subjects. Several other associated SNPs may also regulate ANXA6 expression, according to data obtained from public databases. Higher expression of ANXA6 in patients with SLE was also reported previously. Our study demonstrated the merit of using gene-based analysis to identify novel susceptibility loci, especially those with independent effects, and also demonstrated the widespread presence of loci with independent effects in SLE susceptibility genes.
Fluticasone reduces IL-6 and IL-8 production of cystic fibrosis bronchial epithelial cells<i>via</i>IKK-β kinase pathway
Authors: S. Escotte, O. Tabary, D. Dusser, C. Majer-Teboul, E. Puchelle, J. Jacquot
Journal: European Respiratory Journal (2003)

Inhaled fluticasone propionate (FP) is widely used to reduce pulmonary inflammation in chronic obstructive pulmonary disease, but the potential effects of FP on airway epithelial cells from patients with cystic fibrosis (CF) are unknown. In CF disease, a nonregulated inflammatory lung response occurs through exaggerated nuclear factor (NF)-κB activation and elevated pro-inflammatory cytokines production by airway epithelial cells. To determine whether FP reduces cytokine production in bronchial epithelial cells via NF-κB, the authors investigated the nonstimulated and the Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulated production of NF-κB-dependent interleukin (IL)-6, IL-8 and RANTES (regulated on activation, T-cell expressed and secreted) along with the activation of NF-κB in non-CF and CF human bronchial gland epithelial cells. It was demonstrated that a relevant concentration of FP (10 −8 M) inhibited constitutive and P. aeruginosa LPS-induced IL-6 and IL-8 production of non-CF and CF bronchial epithelial cells. Interestingly, the expression of two IκB kinases (IKK)-α/β, the degradation of cytosolic IκB-β inhibitor and the NF-κB deoxyribonucleic acid binding activity were markedly reduced after FP treatment in both CF and non-CF bronchial epithelial cells. It was shown by the authors that fluticasone propionate exerts an anti-inflammatory effect by blocking a signal transduction leading to a reduced level of IκB-α/β kinases in bronchial epithelial cells. In particular the strong effect on the IκB-β kinase, which is known to be elevated in bronchial epithelial cells in cystic fibrosis patients, was observed.
KLF6-SV1 Is a Novel Antiapoptotic Protein That Targets the BH3-Only Protein NOXA for Degradation and Whose Inhibition Extends Survival in an Ovarian Cancer Model
Authors: Analisa DiFeo, Fei Huang, Jaya Sangodkar, Esteban A. Terzo, Devin Leake, Goutham Narla, John A. Martignetti
Journal: Cancer Research (2009)

Defects in apoptosis are not only a hallmark of cancer initiation and progression but can also underlie the development of chemoresistance. How the tightly regulated cascade of protein-protein interactions between members of three competing protein families regulating the apoptotic cascade is subverted in tumor cells is incompletely understood. Here, we show that KLF6-SV1, whose overexpression is associated with poor survival in several different cancers and is an alternatively spliced isoform of the Krüppel-like tumor suppressor KLF6, is a critical prosurvival/antiapoptotic protein. KLF6-SV1 binds the proapoptotic BH3-only protein NOXA, which results in their mutual HDM2-dependent degradation. In turn, this increases the intracellular concentration of the prosurvival binding partner of NOXA, Mcl-1, and effectively blocks apoptosis. In an ovarian cancer model, systemically delivered small interfering RNA against KLF6-SV1 induces spontaneous apoptosis of tumor cells, decreases tumor burden, and restores cisplatin sensitivity in vivo. Moreover, i.p. delivery of siKLF6-SV1 RNA halts ovarian tumor progression and improves median and overall survival (progression-free for >15 months; P < 0.0002) in mice in a dose-dependent manner. Thus, KLF6-SV1 represents a novel regulator of protein interactions in the apoptotic cascade and a therapeutically targetable control point.
Staphylococcal septic arthritis in rabbits
Authors: B. M ROTHSCHILD;, A J WYSENBEEK
Journal: Annals of the Rheumatic Diseases (1999)

Staphylococcal septic arthritis in rabbitsThe article by Wysenbeek et al 1 provides intriguing insights to the 15 day rabbit Staphylococcus epidermidis infectious arthritis model.However, challenge must be made to their conclusion that injection of corticosteroids into the infected joint seems to be harmless, in the setting of infectious arthritis.Several issues render this model unacceptable for establishing safety of intra-articular corticosteroids in the setting of infectious arthritis.Staphylococcus epidermidis has low infectivity and pathogenicity compared with most articular pathogens. [2]3][4] If you were to consider use of intra-articular corticosteroids as rendering the patient equivalent to the immunosuppressed patient, reduction of synovitis and proteoglycan depletion might be of interest.Of course, use of corticosteroids might change the use of the injected joint, assessment of which probably would require additional controls.The real question seems to be what happens to the joint after antibiotic (and intra-articular corticosteroid) treatment.Analysis two weeks, two months, and six months post-treatment would seem important to identify clinically important eVects of intra-articular corticosteroids.One technical question seems appropriate.How were the section sites selected?The blinding does not seem to have taken place until after the slides were prepared.More detail on the selection process might provide insights as to whether "prime sites" were selected or if the same exact cuts were made in all knees.The study by Wysenbeek et al 1 provides insights to eVect of short-term intra-articular corticosteroids on a low pathogenicity/low infectivity form of infectious arthritis.It is unclear if their conclusion about corticosteroid safety can be extrapolated to organisms of high infectivity/pathogenicity and to clinically significant impact.
Centralized databases available for describing primary brain tumor incidence, survival, and treatment: Central Brain Tumor Registry of the United States; Surveillance, Epidemiology, and End Results; and National Cancer Data Base
Authors: F G Davis, B J McCarthy, M S Berger
Journal: Neuro-Oncology (1999)

Characteristics of three databases—the Central Brain Tumor Registry of the United States (CBTRUS) database; the Surveillance, Epidemiology and End Results (SEER) database; and the National Cancer Data Base (NCDB)— containing information on primary brain tumors are discussed. The recently developed population-based CBTRUS database comprises incidence data on all primary brain tumors from 11 collaborating state registries; however, follow-up data are not available. SEER, the population-based gold standard for cancer data, collects incidence and follow-up data on malignant brain tumors only. While not population-based, the NCDB identifies newly diagnosed cases and conducts follow-up on all primary brain tumors from hospitals accredited by the American College of Surgeons. The NCDB is the largest of the three databases and also contains more complete information regarding treatment of these tumors than either the SEER or CBTRUS databases. Additional strengths and limitations of each of these are described, and their judicious use for supporting research, education, and health care planning is encouraged.
Increased nitric oxide in exhaled air in patients with rheumatic heart disease
Authors: Zehra Gölbaşl, Sibel Dinçer, Hakan Bayol, Belgizar Uğurlu, Dilek Çiçek, Telat Keleş, Sinan Aydoğdu, Deniz Erbaş
Journal: European Journal of Heart Failure (2001)
Analysis of flow vortices in the pulmonary artery of healthy volunteers and patients with pulmonary hypertension
Authors: Guilhem Collier, Andy Swift, David Capener, David Kiely, Robin Condliffe, Charlie Elliot, Jim Wild
Journal: European Respiratory Journal (2013)

Background: 4D flow MRI can be used to assess flow patterns in the blood circulation of the major vessels. It has been applied to pulmonary hypertension (PH) by Reiter, G. et al. (Circulation: Cardiovascular Imaging 2008; 1:23-30), who concluded that manifest PH coincides with the appearance of a vortex of blood flow in the main pulmonary artery (PA) with high sensitivity and specificity, and that the relative lifetime of the vortex (tv) correlates significantly with mean pulmonary arterial pressure (mPAP).  Aims: The present study aims to assess the existence and formation of the vortices in healthy volunteers and patients with suspected PH.  Methods: Subjects undergoing cardiac catheterisation (RHC) at a PH referral centre and healthy volunteers underwent 4D flow MR imaging of the pulmonary artery on a GE HDx 1.5T scanner within 48 hrs of RHC. Velocity maps of the flow in the PA for each cardiac frame were generated. tv was determined by a single observer blinded to the catheter results.  Results: 20 patients with PH (57 ± 30 y), 5 patients with no PH (64 ± 22 y) and 7 healthy subjects (32 ± 9 y) were assessed. Vortices were found in 3 of the 7 healthy subjects and 3 of the 5 healthy patients (mPAP   Conclusion: Vortices of blood flow in the PA are present not only in PH but also in a significant percentage of healthy subjects and patients without PH. Our results in PH patients do not show any correlation between tv and mPAP, which suggests that the existence of a PA flow vortex is not a sensitive parameter for the detection of PH.
Effect of sleep deprivation on overnight bronchoconstriction in nocturnal asthma.
Authors: B Mossberg, K Larsson
Journal: Thorax (1987)

Effect of sleep deprivation on overnight bronchoconstriction in nocturnal asthma SIR, The paper by Dr JR Catterall and others (September 1986;41:676-80) on the overnight fall of FEV1 in a group of 12 asthmatics on a night awake compared with a night asleep is an interesting contribution to a challenging field of research.The authors' conclusion that sleep is an important factor in determining overnight bronchoconstriction in noc- turnal asthma seems, however, not quite justified since another potentially important factor was not controlled in the study: posture itself.It is apparent from the paper that the patients were spending a part of their time lying supine even on the night when they were kept awake.Thus there is a possibility that the greater fall in FEV1 on the "asleep night" was due to a longer time in the lying position.The authors touch on this possibility in the discussion, but imme- diately dismiss it by reference to a work by Clark and Hetzel1 in which asthmatics stated to be kept in bed over the day still developed a morning dip.This work has been widely quoted
Diabetes Quality of Care and Outpatient Utilization Associated With Electronic Patient-Provider Messaging: A Cross-Sectional Analysis
Authors: Lynne T. Harris, Sebastien J. Haneuse, Diane P. Martin, James D. Ralston
Journal: Diabetes Care (2009)

OBJECTIVE To test the hypothesis that electronic patient-provider messaging is associated with high care quality for diabetes and lower outpatient utilization. RESEARCH DESIGN AND METHODS We conducted a cross-sectional analysis of electronic patient-provider messaging over a 15-month period between 1 January 2004 and 31 March 2005. The study was set at Group Health Cooperative—a consumer-governed, nonprofit health care system that operates in Washington and Idaho. Participants included all patients aged ≥18 years with a diagnosis of diabetes. In addition to usual care, all patients had the option to use electronic messaging to communicate with their care providers. The primary outcome measures were diabetes-related quality-of-care indicators (A1C, blood pressure, and LDL cholesterol) and outpatient visits (primary care, specialty care, and emergency). RESULTS Nineteen percent of patients with diabetes used electronic messaging to communicate with their care providers during the study period (n = 2,924) (overall study cohort: 15,427 subjects). In multivariate models, frequent use of electronic messaging was associated with A1C &amp;lt;7% (relative risk [RR] 1.36 [95% CI 1.16–1.58]). Contrary to our hypothesis, frequent use of electronic messaging was also associated with a higher rate of outpatient visits (1.39 [1.26–1.53]). CONCLUSIONS Frequent use of electronic secure messaging is associated with better glycemic control and increased outpatient utilization. Electronic patient-provider communication may represent one strategy to meet the health care needs of this unique population. More research is necessary to assess the effect of electronic messaging on care quality and utilization.
Recognition of class I major histocompatibility complex molecules by Ly-49: specificities and domain interactions.
Authors: J Brennan, G Mahon, D L Mager, W A Jefferies, F Takei
Journal: The Journal of Experimental Medicine (1996)

Ly-49 is a family type II transmembrane proteins encoded by a gene cluster on murine chromosome 6. One member of this family, Ly-49A, is expressed by a natural killer (NK) cell subset, binds to class I major histocompatibility complex (MHC) molecules, and blocks the killing of target cells bearing the appropriate H-2 antigens. Here we show that another member of this family which is expressed by an NK cell subset, Ly-49C, recognizes H-2b and H-2d structures which are distinct from and overlapping with those recognized by Ly-49A. Interactions between Ly-49A and C and their class I ligands are entirely blocked by the antibodies 5E6, YE1/48, YE1/32, and A1, all of which were found to recognize epitopes contained within the carbohydrate recognition domain (CRD). However, cell-cell binding assays revealed that class I binding specificity is conferred by a combination of sequences within both the CRD and a 19-amino acid adjacent region. We also investigated the question of whether Ly-49A and C form dimers on cells which express both receptors. When coexpressed on COS cells, sequential immunoprecipitation demonstrated that these receptors pair exclusively as homodimers, with no evidence for heterodimeric structures. These observations provide insight into both the biochemical nature of the Ly-49 family as well as the receptor functions of Ly-49C on NK cells.
In vivo models of primary brain tumors: pitfalls and perspectives
Authors: P. C. Huszthy, I. Daphu, S. P. Niclou, D. Stieber, J. M. Nigro, P. O. Sakariassen, H. Miletic, F. Thorsen, R. Bjerkvig
Journal: Neuro-Oncology (2012)

Animal modeling for primary brain tumors has undergone constant development over the last 60 years, and significant improvements have been made recently with the establishment of highly invasive glioblastoma models. In this review we discuss the advantages and pitfalls of model development, focusing on chemically induced models, various xenogeneic grafts of human cell lines, including stem cell-like cell lines and biopsy spheroids. We then discuss the development of numerous genetically engineered models available to study mechanisms of tumor initiation and progression. At present it is clear that none of the current animal models fully reflects human gliomas. Yet, the various model systems have provided important insight into specific mechanisms of tumor development. In particular, it is anticipated that a combined comprehensive knowledge of the various models currently available will provide important new knowledge on target identification and the validation and development of new therapeutic strategies.
Correspondence in relation to critical appraisal by Chapman et al
Authors: M. J. Peters, C. R. Jenkins
Journal: Thorax (2010)

Helminth parasites remain one of the most common causes of infections worldwide, yet little is still known about the immune signaling pathways that control their expulsion. C57BL/6 mice are chronically susceptible to infection with the gastrointestinal helminth parasite <i>Heligmosomoides polygyrus</i>. In this article, we report that C57BL/6 mice lacking the adapter protein MyD88, which mediates signaling by TLRs and IL-1 family members, showed enhanced immunity to <i>H. polygyrus</i> infection. Alongside increased parasite expulsion, MyD88-deficient mice showed heightened IL-4 and IL-17A production from mesenteric lymph node CD4<sup>+</sup> cells. In addition, MyD88<sup>−/−</sup> mice developed substantial numbers of intestinal granulomas around the site of infection, which were not seen in MyD88-sufficient C57BL/6 mice, nor when signaling through the adapter protein TRIF (TIR domain–containing adapter–inducing IFN-β adapter protein) was also ablated. Mice deficient solely in TLR2, TLR4, TLR5, or TLR9 did not show enhanced parasite expulsion, suggesting that these TLRs signal redundantly to maintain <i>H. polygyrus</i> susceptibility in wild-type mice. To further investigate signaling pathways that are MyD88 dependent, we infected IL-1R1<sup>−/−</sup> mice with <i>H. polygyrus.</i> This genotype displayed heightened granuloma numbers compared with wild-type mice, but without increased parasite expulsion. Thus, the IL-1R–MyD88 pathway is implicated in inhibiting granuloma formation; however, protective immunity in MyD88-deficient mice appears to be granuloma independent. Like IL-1R1<sup>−/−</sup> and MyD88<sup>−/−</sup> mice, animals lacking signaling through the type 1 IFN receptor (i.e., IFNAR1<sup>−/−</sup>) also developed intestinal granulomas. Hence, IL-1R1, MyD88, and type 1 IFN receptor signaling may provide pathways to impede granuloma formation in vivo, but additional MyD88-mediated signals are associated with inhibition of protective immunity in susceptible C57BL/6 mice.
Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture
Authors: Jordi Muntané-Relat, Jean-Claude Ourlin, Jacques Domergue, Patrick Maurel
Journal: Hepatology (1995)

We have investigated the effect of cytokines, including interleukin-6 (Il-6), interleukin-1 alpha (Il-1 alpha), and tumor necrosis factor-alpha (TNF-alpha), on the inducible expression of cytochrome P450s (CYP) CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. The ability of these cultures to mimic the acute phase response when stimulated with cytokines was evaluated using immunoblotting to measure the production of albumin, ferritin, fibrinogen, and ceruloplasmin. The cytokines exhibited specific patterns of action on the production of these proteins. Albumin was depressed by all the cytokines. In contrast to Il-6 and Il-1 alpha, TNF-alpha reduced the production of fibrinogen and ceruloplasmin but stimulated the production of ferritin. When cells were treated with the CYP inducer alone, large increases in the expression of CYP1A1 and CYP1A2 by beta-naphthoflavone and of CYP3A4 by rifampicin were observed at messenger RNA (mRNA) and protein levels, by ribonuclease protection and immunoblotting, respectively. When the cells were treated with the inducer plus cytokines, the induction of mRNA was greatly reduced. Again, specific patterns of action were revealed: Il-6 had the most potent effect on CYP3A4, whereas TNF-alpha was the most potent with CYP1A genes. In all cases, changes at the protein levels paralleled changes at the mRNA levels. In cells preinduced with beta-naphthoflavone or rifampicin, the decay with time of the levels of the CYP1A2 or CYP3A4 proteins, after the removal of the inducer, was not affected by cytokines. We conclude that cytokines strongly repress the inducibility of CYP1As and CYP3A4 genes at a transcriptional or a posttranscriptional level, but affect neither the rate of translation of CYP mRNAs nor the rate of degradation of the CYP proteins in these cultures.
Silencing of the Hypoxia-Inducible Cell Death Protein BNIP3 in Pancreatic Cancer
Authors: Jiro Okami, Diane M. Simeone, Craig D. Logsdon
Journal: Cancer Research (2004)

Abstract Hypoxic conditions exist within pancreatic adenocarcinoma, yet pancreatic cancer cells survive and replicate within this environment. To understand the mechanisms involved in pancreatic cancer adaptation to hypoxia, we analyzed expression of a regulator of hypoxia-induced cell death, Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). We found that BNIP3 was down-regulated in nine of nine pancreatic adenocarcinomas compared with normal pancreas despite the up-regulation of other hypoxia-inducible genes, including glucose transporter-1 and insulin-like growth factor-binding protein 3. Also, BNIP3 expression was undetectable even after hypoxia treatment in six of seven pancreatic cancer cell lines. The BNIP3 promoter, which was remarkably activated by hypoxia, is located within a CpG island. The methylation status of CpG dinucleotides within the BNIP3 promoter was analyzed after bisulfite treatment by sequencing and methylation-specific PCR. Hypermethylation of the BNIP3 promoter was observed in all BNIP3-negative pancreatic cancer cell lines and eight of 10 pancreatic adenocarcinoma samples. Treatment of BNIP3-negative pancreatic cancer cell lines with a DNA methylation inhibitor, 5-aza-2′ deoxycytidine, restored hypoxia-induced BNIP3 expression. BNIP3 expression was also restored by introduction of a construct consisting of a full-length BNIP3 cDNA regulated by a cloned BNIP3 promoter. Restoration of BNIP3 expression rendered the pancreatic cancer cells notably more sensitive to hypoxia-induced cell death. In conclusion, down-regulation of BNIP3 by CpG methylation likely contributes to resistance to hypoxia-induced cell death in pancreatic cancer.