tbuckley/cabot-search huggingface dataset:
Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS
Authors: Ruohan Xia, Yajuan Liu, Liuqing Yang, Jozsef Gal, Haining Zhu, Jianhang Jia
Journal: Molecular Neurodegeneration (2012)

Abstract Backgound Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a Drosophila model to examine the toxicity of Fus, its Drosophila orthologue Cabeza (Caz), and the ALS-related Fus mutants. Results Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of caz in Drosophila led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death. Conclusions These data demonstrate that the overexpression of Fus/Caz causes in vivo toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different.
Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension
Authors: Rachel Damico, Todd M. Kolb, Lidenys Valera, Lan Wang, Traci Housten, Ryan J. Tedford, David A. Kass, Nicholas Rafaels, Li Gao, Kathleen C. Barnes, Raymond L. Benza, James L. Rand, Rizwan Hamid, James E. Loyd, Ivan M. Robbins, Anna R. Hemnes, Wendy K. Chung, Eric D. Austin, M. Bradley Drummond, Stephen C. Mathai, Paul M. Hassoun
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Pulmonary arterial hypertension (PAH) is a medically incurable disease resulting in death from right ventricular (RV) failure. Both pulmonary vascular and RV remodeling are linked to dynamic changes in the microvasculature. Therefore, we hypothesized that circulating angiostatic factors could be linked to outcomes and represent novel biomarkers of disease severity in PAH.We sought to determine the relationship of a potent angiostatic factor, endostatin (ES), with disease severity and mortality in PAH. Furthermore, we assessed genetic predictors of ES expression and/or function and their association with outcomes in PAH.We measured levels of serum ES in two independent cohorts of patients with PAH. Contemporaneous clinical data included New York Heart Association functional class, 6-minute-walk distance, invasive hemodynamics, and laboratory chemistries.Serum ES correlated with poor functional status, decreased exercise tolerance, and invasive hemodynamics variables. Furthermore, serum ES was a strong predictor of mortality. A loss-of-function, missense variant in the gene encoding ES, Col18a1, was linked to lower circulating protein and was independently associated with reduced mortality.Our data link increased expression of ES to disease severity in PAH and demonstrate a significant relationship with adverse outcomes. Circulating ES levels can be genetically influenced, implicating ES as a genetically determined modifier of disease severity impacting on survival. These observations support serum ES as a potential biomarker in PAH with the capacity to predict poor outcomes. More importantly, this study implicates Col18a1/ES as a potential new therapeutic target in PAH.
Hyperhomocysteinemia Activates Nuclear Factor-κB in Endothelial Cells via Oxidative Stress
Authors: Kathy K.W. Au-Yeung, Connie W.H. Woo, Fion L. Sung, Johnny C.W. Yip, Yaw L. Siow, Karmin O
Journal: Circulation Research (2003)

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated an important interaction between nuclear factor-kappaB (NF-kappaB) activation and homocysteine (Hcy)-induced chemokine expression in vascular smooth muscle cells and macrophages. The objective of the present study was to investigate the in vivo effect of hyperhomocysteinemia on NF-kappaB activation and the underlying mechanism of Hcy-induced NF-kappaB activation in endothelial cells. Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-kappaB and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. The underlying mechanism of Hcy-induced NF-kappaB activation was investigated in human umbilical cord vein endothelial cells and in human aortic endothelial cells. Incubation of cells with Hcy (100 micromol/L) activated IkappaB kinases (IKKalpha and IKKbeta), leading to phosphorylation and subsequent degradation of IkappaBalpha. As a consequence, NF-kappaB nuclear translocation, enhanced NF-kappaB/DNA binding activity, and increased transcriptional activity occurred. Additional analysis revealed a marked elevation of superoxide anion levels in Hcy-treated cells. Treatment of cells with a superoxide anion scavenger (polyethylene glycol-superoxide dismutase) or IkappaB kinase inhibitor (prostaglandin A(1)) could prevent Hcy-induced activation of IKK kinases and NF-kappaB in endothelial cells. In conclusion, these results suggest that Hcy-induced superoxide anion production may play a potential role for NF-kappaB activation in the early stages of atherosclerosis in the vascular wall via activation of IkappaB kinases.
Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus
Authors: A H Sawalha, K M Kaufman, J A Kelly, A J Adler, T Aberle, J Kilpatrick, E K Wakeland, Q-Z Li, A E Wandstrat, D R Karp, J A James, J T Merrill, P Lipsky, J B Harley
Journal: Annals of the Rheumatic Diseases (2007)

Objective: The aetiology of systemic lupus erythematosus (SLE) is incompletely understood. Both genetic and environmental factors are implicated in the pathogenesis of the disease. Herein, we describe genetic association between SLE and polymorphisms in the interleukin (IL)-21 gene. The reported effect of IL-21 on B-cell differentiation into plasma cells and its effect on dendritic cell maturation and T-cell responses make IL-21 an attractive candidate gene for SLE. Methods: Three single nucleotide polymorphisms (SNPs) in the IL-21 gene were genotyped in a total of 2636 individuals (1318 cases and 1318 controls matched for age, sex and race). Population-based case–control association analyses were performed. Results: We found a genetic association with SLE and two SNPs located within the IL-21 gene (rs907715: χ 2 = 11.55, p&lt;0.001; rs2221903: χ 2 = 5.49, p = 0.019). Furthermore, genotypes homozygous for the risk alleles were more frequent than genotypes homozygous for the non-risk alleles in European–American patients as compared to controls (rs907715 (GG versus AA): odds ratio (OR) = 1.66, p = 0.0049; rs2221903 (GG versus AA): OR = 1.60, p = 0.025). Conclusion: Our findings indicate that IL-21 polymorphism is a candidate association with SLE. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
Downregulation of natural killer cell–activating ligand CD155 by human cytomegalovirus UL141
Authors: Peter Tomasec, Eddie C Y Wang, Andrew J Davison, Borivoj Vojtesek, Melanie Armstrong, Cora Griffin, Brian P McSharry, Rebecca J Morris, Sian Llewellyn-Lacey, Carole Rickards, Akio Nomoto, Christian Sinzger, Gavin W G Wilkinson
Journal: Nature Immunology (2005)
Role of Na+/H+ exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox
Authors: M. Karmazyn, M. P Moffat
Journal: Cardiovascular Research (1993)

Journal Article Role of Na+/H+ exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox Get access Morris Karmazyn, Morris Karmazyn Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario N6A 5C1, Canada: M Karmazyn, M P Moffat. Correspondence to Dr Karmazyn. Search for other works by this author on: Oxford Academic PubMed Google Scholar Margaret P Moffat Margaret P Moffat Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario N6A 5C1, Canada: M Karmazyn, M P Moffat. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 27, Issue 6, June 1993, Pages 915–924, https://doi.org/10.1093/cvr/27.6.915 Published: 01 June 1993 Article history Accepted: 16 December 1992 Published: 01 June 1993
Microsatellite Instability of Endothelial Cell Growth and Apoptosis Genes Within Plexiform Lesions in Primary Pulmonary Hypertension
Authors: Michael E. Yeager, George R. Halley, Heiko A. Golpon, Norbert F. Voelkel, Rubin M. Tuder
Journal: Circulation Research (2001)

Abstract —Primary pulmonary hypertension (PPH) is a frequently fatal disease whose pathobiology is poorly understood. Monoclonal endothelial cell growth is present within plexiform lesions of patients with PPH but not secondary PH because of congenital heart malformations. We hypothesized that endothelial cells within PPH plexiform lesions harbor mutations permissive for clonal cell growth. We found that endothelial cells in PPH plexiform lesions demonstrated microsatellite instability within the human MutS Homolog 2 gene (10 of 20 lesions) and displayed microsatellite site mutations and reduced protein expression of transforming growth factor-β receptor type II (6 of 19 lesions) and Bax (4 of 19 lesions). These results suggest that, in PPH, proliferated endothelial cells have genetic alterations associated with microsatellite instability and concomitant perturbation of growth and apoptosis gene expression akin to neoplasia. The full text of this article is available at http://www.circresaha.org.
Anaesthesia, Elvis, and lawnmowers
Authors: M Dylan Bould
Journal: BMJ (2006)

I was interested to see my specialty in the daily “listed” feature in the Guardian newspaper, which, on 13 September 2006, nominated the following “specialist museums”: Anaesthetic Museum, Barts and The London NHS Trust; Business Card Museum, Pennsylvania, USA; Decoy Duck Museum, Maryland, USA; Dog Collar Museum, Leeds Castle; “Elvis is alive” Museum, Missouri, USA; Hair Museum, Missouri, USA; British Lawnmower Museum, Southport; Museum of Questionable Medical Devices, Minnesota, USA; Mushroom Museum, Saumur, France; Pencil Museum, Cumbria; Potato Museum, Brussels; Quilt Museum, Massachusetts, USA; Sock Museum, Sakata, Japan; Typewriter Museum, West Virginia, USA.

Although I certainly cannot argue with an anaesthetic museum being specialist, I thought it was an interesting association to be listed with the Museum of Questionable Medical Devices (www.mtn.org/quack), which includes a …
Targeting FGFR Signaling in Cancer
Authors: Mehdi Touat, Ecaterina Ileana, Sophie Postel-Vinay, Fabrice André, Jean-Charles Soria
Journal: Clinical Cancer Research (2015)

Abstract The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies. Recently, the field of FGFR targeting has exponentially progressed thanks to the development of novel agents inhibiting FGFs or FGFRs, which had manageable safety profiles in early-phase trials. Promising treatment efficacy has been observed in different types of malignancies, particularly in tumors harboring aberrant FGFR signaling, thus offering novel therapeutic opportunities in the era of precision medicine. The most exciting challenges now focus on selecting patients who are most likely to benefit from these agents, increasing the efficacy of therapies with the development of novel potent compounds and combination strategies, and overcoming toxicities associated with FGFR inhibitors. After examination of the basic and translational research studies that validated the oncogenic potential of aberrant FGFR signaling, this review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents. Clin Cancer Res; 21(12); 2684–94. ©2015 AACR.
Macrophage contributions to ovarian function
Authors: R. Wu
Journal: Human Reproduction Update (2004)

Macrophages are multifunctional cells that play key roles in the immune response and are abundant throughout female reproductive tissues. Macrophages are identified in tissues by their expression of cell surface receptors and can execute diverse functional activities, including phagocytosis and degradation of foreign antigens, matrix dissolution and tissue remodelling, and production and secretion of cytokines, chemokines and growth factors. Their specific localization and variations in distribution in the ovary during different stages of the cycle, as well as their presence in peri‐ovulatory human follicular fluid, suggest that macrophages play diverse roles in intra‐ovarian events including folliculogenesis, tissue restructuring at ovulation and corpus luteum formation and regression. This review presents the existing evidence for the regulation of ovarian function by macrophages and macrophage‐derived products, highlighting the implications of these cells in ovarian diseases, particularly polycystic ovary syndrome, endometriosis and premature ovarian failure.
Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience
Authors: Benjamin Hebraud, Florence Magrangeas, Alice Cleynen, Valerie Lauwers-Cances, Marie-Lorraine Chretien, Cyrille Hulin, Xavier Leleu, Edwige Yon, Gerald Marit, Lionel Karlin, Murielle Roussel, Anne-Marie Stoppa, Karim Belhadj, Laurent Voillat, Laurent Garderet, Margaret Macro, Denis Caillot, Mohamad Mohty, Thierry Facon, Philippe Moreau, Michel Attal, Nikhil Munshi, Jill Corre, Stephane Minvielle, Herve Avet-Loiseau
Journal: Blood (2015)
Improved Identification of von Hippel-Lindau Gene Alterations in Clear Cell Renal Tumors
Authors: Michael L. Nickerson, Erich Jaeger, Yangu Shi, Jeffrey A. Durocher, Sunil Mahurkar, David Zaridze, Vsevolod Matveev, Vladimir Janout, Hellena Kollarova, Vladimir Bencko, Marie Navratilova, Neonilia Szeszenia-Dabrowska, Dana Mates, Anush Mukeria, Ivana Holcatova, Laura S. Schmidt, Jorge R. Toro, Sara Karami, Rayjean Hung, Gary F. Gerard, W. Marston Linehan, Maria Merino, Berton Zbar, Paolo Boffetta, Paul Brennan, Nathaniel Rothman, Wong-Ho Chow, Frederic M. Waldman, Lee E. Moore
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.
Estrogen receptor α (ERα) expression in cartilage is important for the ameliorating effects of estrogen on synovitis, but not joint destruction.
Authors: Cecilia Engdahl, Anna E Börjesson, Annica Andersson, Alexandra Stubelius, Andree Krust, Pierre Chambon, Ulrika Islander, Claes Ohlsson, Hans Carlsten, Marie K Lagerquist
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> Estrogen ameliorates incidence and progression of rheumatoid arthritis.. The aim of this study was to investigate the importance of cartilage-specific ERα expression for the ameliorating effects of estrogen on arthritis. <h3>Methods</h3> Mice with total (total ERα<sup>−/−</sup>) or cartilage-specific (Col2α1-ERα<sup>−/−</sup>) inactivation of ERα and wild-type mice were ovariectomised, treated with estradiol (0.83 µg/day) or placebo and induced with antigen-induced-arthritis (AIA). At termination, knees were collected for histology, synovial cells and splenic T cells were investigated using flow cytometry and T cell proliferation and cytokine production was examined. <h3>Results</h3> Estrogen protected against AIA-induced synovitis and joint destruction in wild-type mice and this was associated with decreased frequencies of inflammatory cells (neutrophils, monocytes/macrophages and T cells) in synovial tissue and decreased systemic T cell proliferation. No estrogenic effect was seen in total ERα deficient mice. In cartilage-specific ERα inactivated mice, estrogen protected against joint destruction and decreased systemic T cell proliferation to a similar extent as in wild-type mice. In contrast, estrogen did not ameliorate synovitis in mice lacking ERα in cartilage. <h3>Conclusions</h3> Estrogen ameliorates both synovitis and joint destruction in AIA via ERα and this decreased severity in arthritis is associated with a decrease in synovial inflammatory cells and decreased T cell proliferation. Interestingly, ERα expression in cartilage is required for the ameliorating estrogenic effects on synovitis but not joint destruction, suggesting different target cells and mechanisms for the estrogenic protection of synovial inflammation and joint destruction.
p53 determination alongside classical prognostic factors in node-negative breast cancer: An evaluation at more than 10-year follow-up
Authors: J.-M. Ferrero, A. Ramaioli, J.-L. Formento, M. Francoual, M.-C. Etienne, I. Peyrottes, F. Ettore, P. Leblanc-Talent, M. Namer, G. Milano
Journal: Annals of Oncology (2000)
Association of Hypothyroidism and Obstructive Sleep Apnea
Authors: VISHESH K. KAPUR, THOMAS D. KOEPSELL, JAMES deMAINE, RICHARD HERT, ROBERT E. SANDBLOM, BRUCE M. PSATY
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Obstructive sleep apnea (OSA) and hypothyroidism are relatively common disorders that have similar clinical features and are thought to be causally linked. We sought to determine the prevalence of previously unrecognized hypothyroidism in a series of patients evaluated for OSA and whether an association between hypothyroidism and OSA was present. Chart review was used to obtain information on thyroid function status, polysomnography results, levothyroxine use, and clinical signs and symptoms in 336 consecutive adult patients who underwent polysomnography for suspected OSA. In addition, levothyroxine use was determined in age- and sex-matched control subjects for the purposes of a case-control study. Among the patients without prior history of hypothyroidism who underwent polysomnography and thyroid function testing, four new cases or 1. 41% (95% CI 0.04-2.78) were found to have subclinical hypothyroidism. Our findings do not support routine thyroid screening by specialists in patients referred for polysomnography. The odds ratio of the association of prior history of hypothyroidism to OSA was 1. 47 (95% CI 0.8-2.8). Limitations in study design may have limited our ability to detect a statistically significant association between OSA and hypothyroidism.
Leukotriene C<sub>4</sub>/D<sub>4</sub>Induces P-Selectin and Sialyl Lewis<sup>x</sup>–Dependent Alterations in Leukocyte Kinetics In Vivo
Authors: Samina Kanwar, Brent Johnston, Paul Kubes
Journal: Circulation Research (1995)

Abstract The objective of this study was to assess the effect of leukotriene C 4 (LTC 4 ) on the flux of rolling leukocytes, leukocyte rolling velocity, and leukocyte adhesion in postcapillary venules in vivo and to study the underlying molecular mechanisms involved. LTC 4 (20 nmol/L) induced a rapid and significant increase in leukocyte rolling flux that was inhibitable by an anti–P-selectin antibody and soluble sialyl Lewis x (sLe x ). LTC 4 also induced a significant reduction in leukocyte rolling velocity, an event that was independent of P-selectin but entirely dependent on sLe x . This LTC 4 -induced reduction in leukocyte rolling velocity was independent of any hemodynamic alterations. Another P-selectin effector, histamine, did not affect leukocyte rolling velocity even at &gt;5000 times the concentration of LTC 4 . Treatment with an anti–L-selectin antibody had no effect on the LTC 4 -induced increase in leukocyte rolling or reduction in rolling velocity. Inhibition of LTC 4 bioconversion to LTD 4 by pretreatment with l -serine (100 μmol/L) prevented the LTC 4 -induced increase in leukocyte rolling flux and the LTC 4 -induced reduction in leukocyte rolling velocity. A subtle, yet significant, increase in leukocyte adhesion was also observed with LTC 4 . Pretreatment with a platelet-activating factor receptor antagonist returned the LTC 4 -induced leukocyte rolling velocity to baseline levels. The addition of a very low concentration of platelet-activating factor (1 nmol/L) induced significant leukocyte adhesion in the presence of LTC 4 but not histamine. This study demonstrates that LTC 4 , via bioconversion to leukotriene D 4 , induces a P-selectin–dependent and sLe x -dependent increase in leukocyte rolling flux and a P-selectin–independent but sLe x -dependent reduction in leukocyte rolling velocity, a parameter that may play an essential role in subsequent leukocyte adhesion.