tbuckley/cabot-search huggingface dataset:
Rac-1 Regulates Nuclear Factor of Activated T Cells (NFAT) C1 Nuclear Translocation in Response to Fcε Receptor Type 1 Stimulation of Mast Cells
Authors: Helen Turner, Manuel Gomez, Edward McKenzie, Antje Kirchem, Andrew Lennard, Doreen A. Cantrell
Journal: The Journal of Experimental Medicine (1998)

Transcription factors of the nuclear factor of activated T cells (NFAT) family play a key role in antigen receptor–mediated responses in lymphocytes by controlling induction of a wide variety of cytokine genes. The GTPases Ras and Rac-1 have essential functions in regulation of NFAT transcriptional activity in the mast cell system, where Fcε receptor type 1 (FcεR1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of FcεR1 activation of NFAT in mast cells. We are able to place Rac-1 in two positions in the signaling network that regulates the assembly and activation of NFAT transcriptional complexes in lymphocytes. First, we show that activity of Rac-1 is required for FcεR1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the FcεR1 is a Rac-dependent but Ras-independent process. This novel signaling role for Rac-1 is distinct from its established regulation of the actin cytoskeleton. Our data also reveal a second GTPase signaling pathway regulating NFAT transcriptional activity, in which Rac-1 mediates a Ras signal. These data illustrate that the GTPase Rac-1 should now be considered as a component of the therapeutically important pathways controlling NFATC1 subcellular localization. They also reveal that GTPases may serve multiple functions in cellular responses to antigen receptor ligation.
Human bronchial smooth muscle cells in culture produce stem cell factor
Authors: O. Kassel, F. Schmidlin, C. Duvernelle, B Gasser, G Massard, N. Frossard
Journal: European Respiratory Journal (1999)

A mast cell infiltration of the bronchial smooth muscle layer has been reported in patients sensitized to common allergens. Stem cell factor (SCF) is a chemotactic and survival factor for mast cells. SCF is expressed as a soluble (sSCF) and a membrane-bound (mSCF) form, after alternative splicing of the exon encoding the proteolytic cleavage site. SCF expression by human bronchial smooth muscle cells in culture was evaluated, comparing it to that of human lung fibroblasts in culture. sSCF released in the culture supernatant was assessed by an enzyme-linked immunosorbent assay. Total SCF messenger ribonucleic acid (mRNA) was measured by competitive polymerase chain reaction (PCR) after reverse transcription. Expression of the two forms of SCF mRNA was assessed by PCR, with primers spanning the alternatively spliced exon. Smooth muscle cells produced sSCF (21.9+/-2.6 pg x mL(-1)), although at lower levels than fibroblasts (35.9+/-3.5 pg x mL(-1)); the expression of total SCF mRNA was also at lower levels than in fibroblasts (8.6+/-0.2 and 19.0+/-2.0 amol x fmol glyceraldehyde 3-phosphate dehydrogenase complementary deoxyribonucleic acid(-1), respectively). However, smooth muscle cells expressed proportionally more (1.7-fold) mSCF mRNA than did fibroblasts. In conclusion, this study shows that bronchial smooth muscle cells express stem cell factor, with a relatively high expression of membrane-bound stem cell factor. This might be related to the presence of mast cells within the bronchial smooth muscle layer, i.e. at the site of bronchoconstriction, with possible implications in the pathophysiology of asthma.
FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress
Authors: Marta Libura, Vahid Asnafi, Angela Tu, Eric Delabesse, Isabelle Tigaud, Florence Cymbalista, Annelise Bennaceur-Griscelli, Patrick Villarese, Gabriel Solbu, Anne Hagemeijer, Kheira Beldjord, Olivier Hermine, Elizabeth Macintyre
Journal: Blood (2003)
Definitions of the Insulin Resistance Syndrome
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2004)

This is the second of two articles covering the 1st World Congress on the Insulin Resistance Syndrome, which was held in Los Angeles, 21–22 November 2003.

Richard Pasternak (Boston, MA) discussed the deliberations that led the National Cholesterol Education Program Adult Treatment Panel (ATP) III to propose a new definition of the metabolic syndrome (1) and the impact of this proposal in heightening awareness of the insulin resistance syndrome (IRS). Coronary heart disease (CHD) is the main cause of death in the developed world, and Pasternak noted that contrary to general perceptions, malignancy is only approximately half as frequent a cause of mortality as CHD among women. The concept of metabolic syndrome extends in a precise way an important subset of patients at high risk for CHD. The definition was created to be clinically practical, evidence based, and applicable to existing datasets. The ATP did not find adequate evidence to recommend routine measurement of insulin sensitivity or of inflammatory markers. The 2-h glucose was not included because it was similarly felt not to add sufficient numbers of persons to justify the additional effort involved. The panel has been criticized for not calling the metabolic syndrome a CHD equivalent, but Pasternak pointed out that at that time there was no evidence that this was the case. Rather, the presence of the metabolic syndrome was felt to accentuate the risk accompanying elevated LDL cholesterol, mediated through existing and emerging risk factors. Clinical trials show evidence for modification of atherogenic dyslipidemia, blood pressure, and the prothrombotic state (with aspirin, which the panel recommended only for persons with CHD but which Pasternak suggested is appropriate for all persons with the syndrome) in persons undergoing LDL-lowering therapy. The primary management strategy should be to reverse its root causes of obesity and physical inactivity, with an …
An Address ON THE VALUE OF OPHTHALMIC SYMPTOMS IN GENERAL DIAGNOSIS AND PROGNOSIS: Delivered before the Richmond Division of the British Medical Association
Authors: R. M. Gunn
Journal: BMJ (1907)

IXIvUOURAL 1353 larynx has a very much more healthy appearance; the vocal cords are practically white, the swelling of the mucous membrane is very much diminished, and her voice Is normal.CASE VI. -
Network Analysis Identifies an HSP90-Central Hub Susceptible in Ovarian Cancer
Authors: Hanqing Liu, Fang Xiao, Ilya G. Serebriiskii, Shane W. O'Brien, Marisa A. Maglaty, Igor Astsaturov, Samuel Litwin, Lainie P. Martin, David A. Proia, Erica A. Golemis, Denise C. Connolly
Journal: Clinical Cancer Research (2013)

Epithelial ovarian cancer (EOC) is usually detected at an advanced stage and is frequently lethal. Although many patients respond to initial surgery and standard chemotherapy consisting of a platinum-based agent and a taxane, most experience recurrence and eventually treatment-resistant disease. Although there have been numerous efforts to apply protein-targeted agents in EOC, these studies have so far documented little efficacy. Our goal was to identify broadly susceptible signaling proteins or pathways in EOC.
Correctness is mandatory in science: response to ‘correct determination of Critical Flicker Frequency is mandatory when comparisons to other tests are made’
Authors: Anita Blanka Tryc, Karin Weissenborn
Journal: Gut (2013)

Kircheis and coauthors suggest ‘inadequate handling of the test’ as reason for the worse sensitivity of the Critical Flicker Frequency (CFF) for diagnosing hepatic encephalopathy (HE) compared with other methods evaluated in our study.1 ,2 Their main criticism aims at our finding of CFF above 50 Hz in healthy controls. They argue that flicker frequencies above 50 Hz ‘cannot be sensed and therefore are invisible for the naked eye …’ referring to a review by Shady et al 3 In fact, Shady et al do not give a clear cut-off at 50 Hz but indicate that ‘… the temporal resolution of a typical observer is limited to a CFF of ≈50 for luminance flicker’. CFF depends on several parameters, such as luminance, wavelength and luminous intensity. In everyday life, the experience of CFF thresholds above …
Idiosyncratic Adverse Drug Reactions: Current Concepts
Authors: Jack Uetrecht, Dean J. Naisbitt
Journal: Pharmacological Reviews (2013)

Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs.
Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia
Authors: Mitchell H. Grayson, Dorothy Cheung, Michelle M. Rohlfing, Robert Kitchens, Daniel E. Spiegel, Jennifer Tucker, John T. Battaile, Yael Alevy, Le Yan, Eugene Agapov, Edy Y. Kim, Michael J. Holtzman
Journal: The Journal of Experimental Medicine (2007)

Respiratory viral infections are associated with an increased risk of asthma, but how acute Th1 antiviral immune responses lead to chronic inflammatory Th2 disease remains undefined. We define a novel pathway that links transient viral infection to chronic lung disease with dendritic cell (DC) expression of the high-affinity IgE receptor (FcεRIα). In a mouse model of virus-induced chronic lung disease, in which Sendai virus triggered a switch to persistent mucous cell metaplasia and airway hyperreactivity after clearance of replicating virus, we found that FceRIa−/− mice no longer developed mucous cell metaplasia. Viral infection induced IgE-independent, type I IFN receptor–dependent expression of FcεRIα on mouse lung DCs. Cross-linking DC FcεRIα resulted in the production of the T cell chemoattractant CCL28. FceRIa−/− mice had decreased CCL28 and recruitment of IL-13–producing CD4+ T cells to the lung after viral infection. Transfer of wild-type DCs to FceRIa−/− mice restored these events, whereas blockade of CCL28 inhibited mucous cell metaplasia. Therefore, lung DC expression of FcεRIα is part of the antiviral response that recruits CD4+ T cells and drives mucous cell metaplasia, thus linking antiviral responses to allergic/asthmatic Th2 responses.
Obesity and Its Association with the Complications of Pregnancy
Authors: R. G. Emerson
Journal: BMJ (1962)

Of recent years much attention has been given to the subject of obesity and in particular its relationship to pre-eclamptifc toxaemia and essential hypertension. Williams (1957) showed that patients who started their pregt?ilt_es with a bigh im* ti?l weight weremore likely to develop toxaemia of pregnancy, while Stewart and Hewitt 09?Q) confirmed these findings and went on to >_how that it occurred less often than average in those who wsre underweight, These latter findings were
The Origin of the Full-time Faculty System
Authors: W. Bruce Fye
Journal: JAMA (1991)

Clinical research has long been viewed as a fragile pursuit requiring special nurturing. The full-time clinical faculty system was introduced in the early 20th century to provide a milieu that would foster clinical investigation. This article, based on extensive archival research, will show that the main goal of the architects of the full-time system was to stimulate research by removing the incentive for medical professors to devote their main energy to practice. The plan was developed by preclinical scientists at The Johns Hopkins Medical School (Baltimore, Md) and was inaugurated there in 1913 with the financial assistance of the Rockefeller General Education Board. As other medical schools adopted traditional academic criteria for appointment and advancement, there were additional incentives for faculty members to undertake research. In the 1920s, the General Education Board yielded to pressure to liberalize its definition of full time and began to support medical schools that implemented what came to be known as the "geographic full-time plan." Increased government support and other factors encouraged the expansion of full-time plans and led to an impressive increase in the output of research. Today, growing pressure on full-time clinical faculty members to generate income from practice for themselves and their institutions threatens the future of clinical research in this country. (<i>JAMA</i>. 1991;265:1555-1562)
Pharmacological characteristics of the non-striated anorectal musculature in cats
Authors: F. Penninckx, R. Kerremans, J. Beckers
Journal: Gut (1973)

The isolated internal anal sphincter from cats shows a myogenic spontaneous rhythmic activity. Basal tension and frequency of contraction waves from internal anal sphincter strips are inhibited by muscarinic and beta-adrenergic receptors and excited by alpha-adrenergic receptors. Isoprenaline in high doses had an alpha-adrenoceptor-stimulating activity in strips from the internal sphincter. The inhibitory muscarinic receptors may be the final effectors in the anorectal reflex. The relaxing effect of acetylcholine on the internal sphincter was sometimes preceded by a temporary contraction due to the interaction of intermingled longitudinal muscle fibres. Rectal circular muscle strips contain excitatory muscarinic receptors and inhibitory alpha- and beta-adrenergic receptors. The same can be said of the strips from the longitudinal muscle layer at the anal canal and at the rectum.
Malaria experts criticise World Bank
Authors: Balaji Ravichandran
Journal: BMJ (2006)

Malaria experts from around the world have accused the World Bank of publishing false statistics and approving ineffective malaria control measures. They have called on the bank to relinquish its funding to other agencies better equipped to fight the disease.

Writing in the online edition of the Lancet , the experts, led by Amir Attaran from the University of Ottawa in Canada, suggested that since the launch of the Roll Back Malaria programme, the bank has consistently decreased the funds it allotted for malaria control programmes around the world, and particularly in Africa.

The World …
Antibodies to modified citrullinated vimentin are associated with severe extra-articular manifestations in rheumatoid arthritis
Authors: Carl Turesson, Linda Mathsson, Lennart T H Jacobsson, Gunnar Sturfelt, Johan Rönnelid
Journal: Annals of the Rheumatic Diseases (2013)

Circulating antibodies against citrullinated peptides are highly specific for rheumatoid arthritis (RA), and associated with RA disease progression.1 ,2 We have previously reported that antibodies to cyclic citrullinated peptides (anti-CCP) are associated with severe extra-articular RA (ExRA) manifestations, although rheumatoid factor (RF) levels seemed to be more important in active ExRA than anti-CCP levels.3

Another RA-related antibody, the anti-Sa antibody, which has been associated with severe joint damage in RA,4 reacts with citrullinated vimentin.5 Most studies have shown that antibodies to modified citrullinated vimentin (anti-MCV) have a higher sensitivity but a lower specificity for RA than anti-CCP, although there are conflicting results.6 To our knowledge, no studies have previously reported on the relation between anti-MCV and severe ExRA.

We enrolled 35 …
Effect of Chymase Inhibition on the Arteriovenous Fistula Stenosis in Dogs
Authors: Denan Jin, Haruhiko Ueda, Shinji Takai, Yukiko Okamoto, Michiko Muramatsu, Masato Sakaguchi, Nobuhisa Shibahara, Yoji Katsuoka, Mizuo Miyazaki
Journal: Journal of the American Society of Nephrology (2005)

It was hypothesized that chymase may participate in hemodialysis vascular access dysfunction, as chymase has been known to be an effective enzyme in the conversion of angiotensin I (Ang I) to Ang II and in the latent TGF-β1 to the active form. An arteriovenous (AV) fistula was created between the brachial artery and vein in dogs. In the AV anastomosis, when the walls of the venous and arterial sides were compared, the eccentric neointimal formation was most evident in the venous wall. Compared with the venous side downstream of the AV anastomosis, a severe neointimal hyperplasia was found in the venous side upstream of the AV anastomosis (intima/media, 153 ± 25%). The chymase- and TGF-β–positive mast cells were markedly accumulated in the proliferous neointima and media. In association with the reduction of chymase expression, a marked decrease in Ang II–, AT<sub>1</sub> receptor–, and TGF-β–positive areas was achieved by NK3201 (a chymase inhibitor) treatment, and the neointima formation (intima/media: region A, 53 ± 9%, <i>P</i> &lt; 0.001; region B, 54 ± 14%, <i>P</i> &lt; 0.001) was also significantly suppressed in this group. Although lisinopril treatment also provided some beneficial effects with regard to the prevention of neointimal formation, the degree was less than that seen with chymase inhibition. These findings indicate that mast cell–derived chymase plays an essential role in the pathogenesis of the AV fistula access failure and that chymase inhibition may be a therapeutic target for the treatment of hemodialysis vascular access dysfunction in clinic settings.
ADULT NEUROGENESIS IN THE MAMMALIAN CENTRAL NERVOUS SYSTEM
Authors: Guo-li Ming, Hongjun Song
Journal: Annual Review of Neuroscience (2005)

Forty years since the initial discovery of neurogenesis in the postnatal rat hippocampus, investigators have now firmly established that active neurogenesis from neural progenitors continues throughout life in discrete regions of the central nervous systems (CNS) of all mammals, including humans. Significant progress has been made over the past few years in understanding the developmental process and regulation of adult neurogenesis, including proliferation, fate specification, neuronal maturation, targeting, and synaptic integration of the newborn neurons. The function of this evolutionarily conserved phenomenon, however, remains elusive in mammals. Adult neurogenesis represents a striking example of structural plasticity in the mature CNS environment. Advances in our understanding of adult neurogenesis will not only shed light on the basic principles of adult plasticity, but also may lead to strategies for cell replacement therapy after injury or degenerative neurological diseases.
Clinical and histopathologic features of 8 patients with microscopic polyangiitis including two with a slowly progressive clinical course
Authors: Tamihiro Kawakami, Takeshi Kawanabe, Chihiro Saito, Maya Kannari, Masako Mizoguchi, Hiroko Nagafuchi, Takahiro Okazaki, Shoichi Ozaki, Kenjiro Kimura, Yoshinao Soma
Journal: Journal of the American Academy of Dermatology (2007)
Pulmonary Inflammatory Myofibroblastic Tumor Expressing a Novel Fusion, PPFIBP1–ALK: Reappraisal of Anti-ALK Immunohistochemistry as a Tool for Novel ALK Fusion Identification
Authors: Kengo Takeuchi, Manabu Soda, Yuki Togashi, Emiko Sugawara, Satoko Hatano, Reimi Asaka, Sakae Okumura, Ken Nakagawa, Hiroyuki Mano, Yuichi Ishikawa
Journal: Clinical Cancer Research (2011)

The anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been used in patients with lung cancer or inflammatory myofibroblastic tumor (IMT), both types harboring ALK fusions. However, detection of some ALK fusions is problematic with conventional anti-ALK immunohistochemistry because of their low expression. By using sensitive immunohistochemistry, therefore, we reassessed "ALK-negative" IMT cases defined with conventional immunohistochemistry (approximately 50% of all examined cases).Two cases of ALK-negative IMT defined with conventional anti-ALK immunohistochemistry were further analyzed with sensitive immunohistochemistry [the intercalated antibody-enhanced polymer (iAEP) method].The two "ALK-negative" IMTs were found positive for anti-ALK immunohistochemistry with the iAEP method. 5'-rapid amplification of cDNA ends identified a novel partner of ALK fusion, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1 (PPFIBP1) in one case. The presence of PPFIBP1-ALK fusion was confirmed with reverse transcriptase PCR, genomic PCR, and FISH. We confirmed the transforming activities of PPFIBP1-ALK with a focus formation assay and an in vivo tumorigenicity assay by using 3T3 fibroblasts infected with a recombinant retrovirus encoding PPFIBP1-ALK. Surprisingly, the fusion was also detected by FISH in the other case.Sensitive immunohistochemical methods such as iAEP will broaden the potential value of immunohistochemistry. The current ALK positivity rate in IMT should be reassessed with a more highly sensitive method such as iAEP to accurately identify those patients who might benefit from ALK-inhibitor therapies. Novel ALK fusions are being identified in various tumors in addition to IMT, and thus a reassessment of other "ALK-negative" cancers may be required in the forthcoming era of ALK-inhibitor therapy.
The evaluation of asthma control after the March 11, 2011 complex disaster of earthquake, tsunami, and nuclear power plant accident
Authors: Atsuro Fukuhara, Suguru Sato, Manabu Uematsu, Kenichi Misa, Takefumi Nikaido, Naoko Fukuhara, Xintao Wang, Kenya Kanazawa, Yoshinori Tanino, Takashi Ishida, Mitsuro Munakata
Journal: European Respiratory Journal (2013)

Background; The Great East Japan Earthquake and tsunami on March 11, 2011, resulted in the Fukushima nuclear power plant accident, which consequently led to a massive emission of radioactive substances. This matchless complex disaster is presumed to have had a huge impact on asthmatics.  Objectives; We evaluated the physical and psychological status of asthmatics until one year later after the disaster.  Methods; Seventy asthmatics were enrolled and performed a questionnaire about the disaster just after and one year later.  Results; Six patients could not continue inhaled corticosteroids (ICS) by the loss of medicine. In these 6 patients, four patients (66.7%) had an asthmatic attack just after that the disaster. On the other hand, an asthmatic attack was caused only in ten patients in 64 patients (15.6%, p  Conclusions; Patients can maintain a good asthma control by continuation of ICS even just after the disaster. In addition, long term psychological support seems to be important to reduce anxiety and keep good asthma control.