tbuckley/cabot-search huggingface dataset:
Identification of a novel population of Langerin+ dendritic cells
Authors: Laura S. Bursch, Liangchun Wang, Botond Igyarto, Adrien Kissenpfennig, Bernard Malissen, Daniel H. Kaplan, Kristin A. Hogquist
Journal: The Journal of Experimental Medicine (2007)

Langerhans cells (LCs) are antigen-presenting cells that reside in the epidermis of the skin and traffic to lymph nodes (LNs). The general role of these cells in skin immune responses is not clear because distinct models of LC depletion resulted in opposite conclusions about their role in contact hypersensitivity (CHS) responses. While comparing these models, we discovered a novel population of LCs that resides in the dermis and does not represent migrating epidermal LCs, as previously thought. Unlike epidermal LCs, dermal Langerin+ dendritic cells (DCs) were radiosensitive and displayed a distinct cell surface phenotype. Dermal Langerin+ DCs migrate from the skin to the LNs after inflammation and in the steady state, and represent the majority of Langerin+ DCs in skin draining LNs. Both epidermal and dermal Langerin+ DCs were depleted by treatment with diphtheria toxin in Lang-DTREGFP knock-in mice. In contrast, transgenic hLang-DTA mice lack epidermal LCs, but have normal numbers of dermal Langerin+ DCs. CHS responses were abrogated upon depletion of both epidermal and dermal LCs, but were unaffected in the absence of only epidermal LCs. This suggests that dermal LCs can mediate CHS and provides an explanation for previous differences observed in the two-model systems.
Case number 33: About being a famous European and suffering from gout.....
Authors: A Boonen
Journal: Annals of the Rheumatic Diseases (2005)

The Annals of the Rheumatic Diseases , the official EULAR journal, appreciates the European dimension of rheumatology. One of the people who had an important role in the old continent was Charles V (Ghent, Flanders 1500, + San Yuste, Spain 1558). Although his policy did not always favour a unified Europe, the history of his life and illnesses are closely linked with many European countries.

We can learn about details of his illness and complaints from the letters he wrote to his sister Mary of Hungary, widow of the Hungarian king and governess of the Spanish Netherlands.1 In 1532 he describes in one of these …
Cladribine treatment of multiple sclerosis
Authors: Chris H. Polman, Johan C. Koetsier, David Reilly, Jack Sipe, James Koziol, John Romine, Ernest Beutler, Pawel Grieb, Miroslaw Ryba, Zbigniew Stelmasiak, Jacek Nowicki, Janusz Solski, Beata Jakubowska
Journal: The Lancet (1994)
Smooth muscle cells deficient in osteopontin have enhanced susceptibility to calcification in vitro
Authors: M SPEER, Y CHIEN, M QUAN, H YANG, H VALI, M MCKEE, C GIACHELLI
Journal: Cardiovascular Research (2005)

Vascular calcification is an actively regulated process, correlating with cardiovascular morbidity and mortality especially in patients with diabetes and chronic renal diseases. Osteopontin (OPN) is abundantly expressed in human calcified arteries and inhibits vascular calcification in vitro and in vivo. How OPN functions in vascular calcification, however, is less clear.Smooth muscle cells (SMCs) were isolated from aortas of OPN knock-out (OPN-/-) and wild type (OPN+/+) mice.OPN-/- SMCs were identical to OPN+/+ SMCs in morphology and stained positively for SM lineage proteins, desmin, smooth muscle alpha-actin and SM22alpha. No spontaneous calcification was observed in OPN-/- SMCs under normal culture conditions or in medium containing 1%, 3%, or 5% fetal bovine serum. However, when cultured in medium containing elevated concentrations of inorganic phosphate, an inducer of vascular calcification, a significantly higher calcification was observed in OPN-/- SMCs compared to OPN+/+ SMCs that, in response to elevated phosphate, synthesized and secreted OPN into the culture. Finally, retroviral transduction of mouse OPN cDNA into OPN-/- SMCs rescued the calcification phenotype of the cells.These results are the first to demonstrate an inhibitory role of endogenously produced OPN on SMC calcification, suggesting a novel feedback mechanism where OPN produced locally by the SMCs may serve as an important inducible inhibitor of vascular calcification.
Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure
Authors: G Kojda
Journal: Cardiovascular Research (1999)

There is a growing body of evidence suggesting that numerous pathological conditions are associated with increased vascular production of reactive oxygen species. This form of vascular oxidant stress and particularly interactions between NO and oxygen-derived radicals represent a common pathological mechanism present in many so-called risk factors for atherosclerosis. Furthermore, reactive oxygen species seem to serve important cellular signalling mechanisms responsible for many of the features of vascular lesion formation. The mechanisms whereby vascular cells produce reactive oxygen species are only presently coming to light, and almost certainly will prove to be a focus for future therapies.
Mutations in PTF1A cause pancreatic and cerebellar agenesis
Authors: Gabrielle S Sellick, Karen T Barker, Irene Stolte-Dijkstra, Christina Fleischmann, Richard J Coleman, Christine Garrett, Anna L Gloyn, Emma L Edghill, Andrew T Hattersley, Peter K Wellauer, Graham Goodwin, Richard S Houlston
Journal: Nature Genetics (2004)
Mutation of Genes Affecting the RAS Pathway Is Common in Childhood Acute Lymphoblastic Leukemia
Authors: Marian Case, Elizabeth Matheson, Lynne Minto, Rosline Hassan, Christine J. Harrison, Nick Bown, Simon Bailey, Josef Vormoor, Andrew G. Hall, Julie A.E. Irving
Journal: Cancer Research (2008)

Abstract Deregulation of the RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK signaling cascade is often caused by somatic mutations in genes encoding proteins which influence the activity of this pathway and include NRAS, KRAS2, FLT3, PTPN11, and BRAF. We report the first comprehensive mutational screen of key exons of these genes in a large cohort of unselected acute lymphoblastic leukemia (ALL) cases at diagnosis (n = 86) and in a more selected cohort at disease recurrence (n = 47) using the sensitive method of denaturing high-performance liquid chromatography. We show that somatic mutations that deregulate the pathway constitute one of the most common genetic aberrations in childhood ALL (cALL), being found in 35% of diagnostic and 25% of relapse samples. In matched presentation/relapse pairs, mutations predominating at relapse could be shown to be present at very low levels at diagnosis using allele-specific PCR, thus implicating the mutated clone in disease progression. Importantly, in primary samples, we show that mutations are associated with activated ERK and differential cytotoxicity to MEK-ERK inhibitors was shown for some patients. Inhibitors of the pathway, which are currently undergoing clinical trial, may be a novel therapeutic option for cALL, particularly at relapse. [Cancer Res 2008;68(16):6803–9]
THE RELATIONSHIP BETWEEN SPREADING FACTOR AND HYALURONIDASE
Authors: Gladys L. Hobby, Martin H. Dawson, Karl Meyer, Eleanor Chaffee
Journal: The Journal of Experimental Medicine (1941)

A comparative study of spreading factor and hyaluronidase in preparations from various sources revealed the following points of similarity and dissimilarity in the two reactions. 1. Similarities: (a) All preparations containing hyaluronidase also produced spreading. (b) Heating at 65 degrees and 100 degrees C. for 30 minutes produced a comparable effect on both reactions. (c) The demonstration of the presence of hyaluronic acid in skin offers a plausible explanation for the mechanism of spreading on the basis of hyaluronidase activity. 2. Dissimilarities: (a) No parallelism was observed in the degree of activity of spreading factor and hyaluronidase in the same preparations. (b) All preparations which produced spreading did not contain hyaluronidase. (c) Antisera to hyaluronidase preparations specifically and completely inhibited the activity of the homologous enzyme but did not inhibit the spreading factor in the same preparations. The significance of the similarities and dissimilarities between the two reactions is discussed. It is concluded that while hyaluronidase may play a rôle in the spreading reaction the phenomenon is a complex one and cannot be explained on the basis of a simple chemical reaction.
Trends in Racial and Age Disparities in Definitive Local Therapy of Early-Stage Breast Cancer
Authors: Rachel A. Freedman, Yulei He, Eric P. Winer, Nancy L. Keating
Journal: Journal of Clinical Oncology (2008)

Guidelines recommend breast-conserving surgery (BCS) with radiation or mastectomy for definitive local therapy of stage I/II breast cancers. We assessed receipt of definitive local therapy for early-stage breast cancer by race/ethnicity and age and examined trends over time.We calculated rates of definitive local therapy (mastectomy or BCS with radiation) for 375,547 adult women with stage I or II breast cancer diagnosed during 1988 to 2004 using Surveillance, Epidemiology, and End Results registry data. We assessed the probability of definitive local therapy and trends over time using multivariate logistic regression.Overall, 85.8% of women had definitive local therapy. As mastectomy rates decreased (76.5% in 1988 to 38.0% in 2004; P < .001), definitive local therapy rates also decreased (95.2% in 1988 to 79.2% in 2004; P < .001). In adjusted analyses, rates of definitive local therapy were modestly lower for black and Hispanic (v white) women and higher for Asian women. Differences for black and Asian women were stable over time (P = .61 and P = .35 for interaction), but increased for Hispanic women (P = .0003). Although age differences narrowed over time, women older than 70 years and women <or= 60 years had lower rates of definitive local therapy than women 61 to 70 years throughout the study period.As breast conservation has increasingly substituted mastectomy, our findings suggest fewer women are receiving definitive local breast cancer therapy, with persistent disparities for black and Hispanic women as well as women age <or= 60 and older than 70 years. Interventions to assure receipt of radiation after BCS are needed to eliminate these disparities.
Effects of tongue electrical stimulation on pharyngeal mechanics in anaesthetized patients with obstructive sleep apnoea
Authors: S Isono, A Tanaka, T Nishino
Journal: European Respiratory Journal (1999)

The tongue plays a significant role in the maintenance of a patent airway. The purpose of this study was to examine the effects of tongue musculature contraction on the static mechanical properties of the pharynx in patients with obstructive sleep apnoea (OSA). During hyperventilation-induced apnoea in seven OSA patients anaesthetized with sevoflurane, the static pressure/area relationships of the oropharynx were obtained by means of step changes in airway pressure while endoscopically measuring cross-sectional area. At each airway pressure, the tongue was electrically stimulated via electrodes placed bilaterally. Tongue electrical stimulation (TES) did not further dilate the oropharyngeal area at higher airway pressure (3.2+/-1.9 versus 3.0+/-2.1 cm2), although the narrowed oropharyngeal area at lower airway pressures increased during TES (0.8+/-9.0) versus 1.7+/-1.8 cm2, p&lt;0.05). Accordingly, the slope of the pressure/area relationship decreased during TES (0.24+/-0.20 versus 0.12+/-0.09 cm2 x cm H2O(-1), p&lt;0.05). In conclusion, electrical stimulation of the tongue stiffens the retroglossal airway wall in patients with obstructive sleep apnoea.
From the Museum: the Art of Thinking. Part Six: Perception
Authors: Tom Kotsimbos
Journal: European Respiratory Journal (2014)

Starry Night is as famous the world over as its creator was obscure. It is both a mirror of its time and the perpetually troubled soul that created it. The night sky is deconstructed into deepened blues and lightened violets (technical immediacy of Impressionism) and reassimilated into a myriad of energised linear swirls and vibrating pulses of yellow-orange radiating out from variably hot centres as a means of revealing an ecstatic inner vision (expressive power of Post-Impressionism). The emotionally charged night sky is pierced by an upward-reaching, flame-swirling, cypress tree (cemetery association) depicted as a dark green silhouette bordering the shadowy coolness of the sleeping village below. The simplicity and sophistication of this image invites us to reflect deeply on Van Gogh's comment that "…death is the road we take to reach the stars…" expressed with sincere clarity during a moment of visionary enlightenment within a period of asylum darkness. For the Impressionists, optical realism separated visual experience from memory, cultivating an extreme indifference to pictorial content. Sunlight was broken down to its primary colours which were then recombined with short, rapid brush stokes capturing the immediacy of the fleeting moment.
Advanced Glycation End Products Inhibit Tubulogenesis and Migration of Kidney Epithelial Cells in an Ezrin-Dependent Manner
Authors: Marisa A Gallicchio, E. Anne McRobert, Anjali Tikoo, Mark E. Cooper, Leon A. Bach
Journal: Journal of the American Society of Nephrology (2005)

Nonenzymatic glycation of proteins to form advanced glycation end products (AGE) is implicated in diabetic complications, including nephropathy. It was shown recently that AGE bind to the ERM (ezrin, radixin, and moesin) family of membrane-cytoskeletal linker proteins in renal homogenates. Herein is reported the effects of AGE-BSA on ezrin-dependent LLC-PK1 kidney epithelial cellular functions: migration and hepatocyte growth factor (HGF)-induced tubulogenesis. LLC-PK1 cells were stably transfected with cDNA for ezrin sense, ezrin antisense, and N-ezrin. Transfection of LLC-PK1 cells with ezrin antisense and dominant negative N-ezrin decreased basal tubulogenesis and migration relative to vector-only transfection, establishing the ezrin dependency of these processes. AGE-BSA (20 or 40 microM) significantly decreased HGF-induced tubulogenesis and basal migration in two vector control lines relative to BSA-treated cells. However, AGE-BSA inhibition of both HGF-induced tubulogenesis and migration was overcome by overexpressing ezrin. These results demonstrate that the AGE-ezrin interaction significantly alters cellular function. These changes may be relevant to detrimental renal consequences as a result of diabetes.
Changes in pancreatic morphology associated with aging
Authors: L. Kreel, B. Sandin
Journal: Gut (1973)

Retrograde pancreatography has been carried out at necropsy in 120 cases and the results have been analysed in statistical detail. With increasing age, changes in pancreatic anatomy occur which must not be taken to indicate pathology. These changes are: (1) low or ptotic position of the pancreas so that the papilla of Vater is below the level of L3; (2) calcification of the splenic and superior mesenteric arteries which produce calcific densities around the pancreas; (3) increasing width of main pancreatic duct along its whole length at about 8% per decade; in the elderly, widths of 1 cm can occur in the main duct in the head of the pancreas without evidence of obstruction; (4) formation of ductular ectasia which affects mainly the interlobular ductules but also intralobular ductules; (5) some ectatic ducts reach the dimensions of cysts, ie, 1-2 cm in diameter. Other morphological changes which have been demonstrated and which may produce difficulties in radiological interpretation are: (<i>a</i>) narrowed ducts not due to stricture; (<i>b</i>) space-occupying lesions due to superior mesenteric artery, splenic artery, aorta, vertebral osteophytes, sympathetic ganglion, and lymph nodes; (<i>c</i>) metastases in the pancreas—these must be distinguished from primary pancreatic carcinoma. The implications of these findings for endoscopy and isotope pancreatic scanning will be mentioned.
Structure–function relationships of vitamin D including ligand recognition by the vitamin D receptor
Authors: Sachiko Yamada, Masato Shimizu, Keiko Yamamoto
Journal: Medicinal Research Reviews (2002)

Abstract First, the general structure and function of nuclear receptors (NRs) are described briefly to help our understanding of the mechanism of action of vitamin D mediated by the vitamin D receptor (VDR), a member of the NRs. Then we discuss the structure–function relationship (SFR) of vitamin D on the basis of ligand structures and the interaction of the ligand with the VDR. The SFR of vitamin D side chain analogs is discussed extensively in terms of our active space group concept, which was derived from conformational analyses of the side chains of vitamin D analogs and from studies with conformationally restricted 22‐methyl‐1,25‐(OH) 2 D 3 isomers. The mobile area of the side chain of vitamin D can be grouped into five regions (E, G, EA, EG, and F), and the SFR has been analyzed in terms of these spatial regions. The SFR of ligand/VDR interaction is discussed on the basis of the crystal structure of VDR‐LBD(Δ165–215), docking of various vitamin D ligands into the ligand binding pocket (LBP) of the VDR, and functional analysis of amino acids lining the LBP. Finally, we discuss total SFR, combining the results of the two approaches, and future aspects of structure‐based design of vitamin D analogs. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 1, 89–115, 2003; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10023
Simian virus 40 large T antigen (SV40LTAg) primer specific DNA amplification in human pleural mesothelioma tissue.
Authors: C Pepper, B Jasani, H Navabi, D Wynford-Thomas, A R Gibbs
Journal: Thorax (1996)

BACKGROUND: DNA sequences and immunoreactivity associated with Simian virus 40 transforming factors, large T and small t antigens (SV40LTAg), suggestive of an aetiopathogenetic link have been identified in fresh frozen tissue of a high proportion of recent cases of pleural mesotheliomas from the United States, Italy and Germany. SV40 is not normally infective in man though it can transform human cells in tissue culture. A large cohort of people in the western world was accidentally parenterally inoculated with live SV40 through contaminated polio vaccines given between 1959 and 1961, and this might be a factor in the current continuing rise in the incidence of mesothelioma in the United States, Britain and Europe. The present study investigated the presence of SV40LTAg DNA in recently diagnosed cases of mesothelioma in Britain and the feasibility of detecting the SV40 DNA in archival tissue for retrospective analysis of cases in the peri-vaccination period. METHODS: DNA was extracted from fresh frozen and/or rehydrated formalin fixed, paraffin embedded tissue sections from nine recently diagnosed cases of mesothelioma, nine cases of pulmonary adenocarcinoma, and three reactive pleurae, and amplified by the polymerase chain reaction (PCR) using the primer pairs used previously on fresh frozen tissues-namely, the SV primer set directed at the LTAg gene sequence unique to SV40 and the PYV primer set directed at a sequence shared by SV40 and papovavirus strains BK and JC, respectively. RESULTS: PCR positivity with the SV primer set was restricted to four of the nine cases of mesothelioma. In contrast, six of the nine mesotheliomas, two of the nine adenocarcinomas, and one of the three reactive pleurae showed positivity with the PYV primers. The fresh frozen and corresponding formalin fixed, paraffin embedded tissue results concorded well with each other. CONCLUSIONS: Our data provide evidence for the association of SV40LTAg primer specific DNA with human pulmonary mesothelioma in the British population.
Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis
Authors: Shaoping Wu, Yong-guo Zhang, Rong Lu, Yinglin Xia, David Zhou, Elaine O Petrof, Erika C Claud, Di Chen, Eugene B Chang, Geert Carmeliet, Jun Sun
Journal: Gut (2014)

<h3>Objective</h3> Vitamin D and the vitamin D receptor (VDR) appear to be important immunological regulators of inflammatory bowel diseases (IBD). Defective autophagy has also been implicated in IBD, where interestingly, polymorphisms of genes such as ATG16L1 have been associated with increased risk. Although vitamin D, the microbiome and autophagy are all involved in pathogenesis of IBD, it remains unclear whether these processes are related or function independently. <h3>Design</h3> We investigated the effects and mechanisms of intestinal epithelial VDR in healthy and inflamed states using cell culture models, a conditional VDR knockout mouse model (VDR<sup>ΔIEC</sup>), colitis models and human samples. <h3>Results</h3> Absence of intestinal epithelial VDR affects microbial assemblage and increases susceptibility to dextran sulfate sodium-induced colitis. Intestinal epithelial VDR downregulates expressions of ATG16L1 and lysozyme, and impairs antimicrobial function of Paneth cells. Gain and loss-of-function assays showed that VDR levels regulate ATG16L1 and lysozyme at the transcriptional and translational levels. Moreover, low levels of intestinal epithelial VDR correlated with reduced ATG16L1 and representation by intestinal <i>Bacteroides</i> in patients with IBD. Administration of the butyrate (a fermentation product of gut microbes) increases intestinal VDR expression and suppresses inflammation in a colitis model. <h3>Conclusions</h3> Our study demonstrates fundamental relationship between VDR, autophagy and gut microbial assemblage that is essential for maintaining intestinal homeostasis, but also in contributing to the pathophysiology of IBD. These insights can be leveraged to define therapeutic targets for restoring VDR expression and function.
ErbB4 Modulates Tubular Cell Polarity and Lumen Diameter during Kidney Development
Authors: Ville Veikkolainen, Florence Naillat, Antti Railo, Lijun Chi, Aki Manninen, Peter Hohenstein, Nick Hastie, Seppo Vainio, Klaus Elenius
Journal: Journal of the American Society of Nephrology (2011)

ErbB4 receptor tyrosine kinase contributes to the development of the heart, the central nervous system, and the lactating mammary gland, but whether it has a role in the development of the kidney epithelium is unknown. Here, we found that expression of Erbb4 isoforms JM-a CYT-1 and JM-a CYT-2 was first detectable around embryonic day 13 in the mouse, mainly in the collecting ducts and both the proximal and distal tubules. In vitro, overexpression of a relevant ErbB4 isoform promoted proliferation and disturbed polarization of kidney epithelial cells when cultured as three-dimensional structures. We examined ErbB4 function in developing kidney tubules in vivo with Pax8-Cre–mediated conditional overexpression of Rosa26 locus–targeted ERBB4 and with conditional Erbb4 knock-out mice. The Pax8-Cre–driven ERBB4 overexpression enhanced proliferation in the collecting ducts, reduced the size of epithelial duct lumens, and promoted formation of cortical tubular cysts. These defects were associated with changes in the subcellular distribution of markers of epithelial cell polarity. Similarly, the Pax8-Cre–mediated Erbb4 knock-out mice manifested dysfunctional kidneys with larger duct lumens and epithelial cell mispolarization. Taken together, these data suggest that ErbB4 signaling modulates proliferation and polarization, cellular functions critical for the development of epithelial ducts in the kidney.