tbuckley/cabot-search huggingface dataset:
Cellular Responses to Viral Infection in Humans: Lessons from Epstein-Barr Virus
Authors: Andrew D. Hislop, Graham S. Taylor, Delphine Sauce, Alan B. Rickinson
Journal: Annual Review of Immunology (2007)

Epstein-Barr virus (EBV) provides a useful model to study cellular immunity to a genetically stable, persistent human virus. Different sets of proteins expressed during EBV's lytic and cell transforming infections induce qualitatively different cellular immune responses. The factors governing immunodominance hierarchies and the biological effectiveness of these different responses are now being revealed. Analysis of infectious mononucleosis (IM), a clinical syndrome that can arise during primary EBV infection, has allowed the evolution of the responses to be tracked over time, giving an understanding of the immune response kinetics and of those determinants affecting selection into memory. Furthermore, following IM, expression of the receptor for the homeostatic cytokine IL-15 on NK and T cells is lost within these individuals. This experiment of nature provides a system to advance understanding of immunological homeostasis in humans, illustrating how data obtained from the study of EBV have wider significance to the immunological community.
Reflectance confocal microscopy correlates of dermoscopic patterns of facial lesions help to discriminate lentigo maligna from pigmented nonmelanocytic macules
Authors: N. de Carvalho, F. Farnetani, S. Ciardo, C. Ruini, A.M. Witkowski, C. Longo, G. Argenziano, G. Pellacani
Journal: British Journal of Dermatology (2014)

The clinical recognition of lentigo maligna (LM) and LM melanoma can be very challenging due to the overlapping features it shares with other pigmented macules of the skin. Noninvasive diagnostic techniques can assist in the differential diagnosis.To identify reflectance confocal microscopy (RCM) indicators for LM through the identification of in vivo microscopic substrates of the main dermoscopic features seen in flat pigmented lesions of the face.Retrospective analysis of 60 pigmented lesions (LM, invasive melanoma, solar lentigo/flat seborrhoeic keratosis, lichen planus-like keratosis, pigmented actinic keratosis) was carried out. The main dermoscopic patterns and RCM features were described. A new method for correlating RCM with dermoscopic patterns was developed.Pseudonetwork (37 of 60 lesions) and annular granular structures (37 of 60 lesions) were the most frequent dermoscopic patterns, followed by pigmented blotches (27 of 60 lesions). Upon RCM examination, pseudonetwork and blotches differed in melanomas and other nonmelanocytic lesions. These differences included the intraepidermal proliferation of atypical cells (predominantly dendritic-shaped with adnexal tropism) and the presence of a meshwork pattern at the junction. Also, annular granular structures exhibited dendritic cells almost exclusively in melanoma, with no difference between melanomas and nonmelanocytic lesions for the junctional and upper dermal pattern (characterized by dermal inflammation). Fingerprinting was mostly present in nonmelanocytic lesions or corresponded to an overlap with solar lentigo in melanomas.RCM is useful for identifying the histological substrate of dermoscopic features in pigmented lesions of the face. It can provide a better definition of the lesion areas, enabling an improved diagnostic approach.
Benefit-Risk Summary of Nivolumab for Patients With Metastatic Squamous Cell Lung Cancer After Platinum-Based Chemotherapy
Authors: Dickran Kazandjian, Sean Khozin, Gideon Blumenthal, Lijun Zhang, Shenghui Tang, Meredith Libeg, Paul Kluetz, Rajeshwari Sridhara, Patricia Keegan, Richard Pazdur
Journal: JAMA Oncology (2015)

<h3>Importance</h3> Metastatic squamous non–small-cell lung cancer (SQ NSCLC) is a serious and life-threatening malignant condition with unmet medical need. In late December 2014, the US Food and Drug Administration (FDA) obtained the data monitoring committee report of a planned interim analysis of a trial in second-line SQ NSCLC (CM017) that demonstrated an overall survival benefit for patients treated with nivolumab compared with docetaxel. <h3>Observations</h3> In that trial, 272 patients with metastatic SQ NSCLC patients had been randomized to receive nivolumab (n = 135) or docetaxel (n = 137). Median overall survival was 9.2 months for patients randomized to nivolumab and 6.0 months for those randomized to docetaxel (hazard ratio, 0.59; 95% CI, 0.44-0.79;<i>P</i> &lt; .001). The safety of nivolumab was evaluated in a single-arm trial of 117 patients in previously treated metastatic SQ NSCLC and was consistent with the safety profile in melanoma, with rare but serious immune-mediated adverse events managed with corticosteroids and dose interruption. <h3>Conclusions and Relevance</h3> The FDA granted nivolumab traditional approval on March 4, 2015, for treatment of metastatic SQ NSCLC with progression during or after platinum-based chemotherapy. The approval provides an important treatment option for these patients, affecting routine care and clinical trials.
Local removal of phagocytic synovial lining cells by clodronate-liposomes decreases cartilage destruction during collagen type II arthritis
Authors: P L E M Van Lent, A E M Holthuysen, N Van Rooijen, L B A V. De Putte, W B V. Den Berg
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVE</h3> To investigate whether local removal of phagocytic synovial lining cells (SLCs) from the knee joint before onset of collagen type II arthritis has an effect on development of cartilage destruction. <h3>METHODS</h3> Phagocytic SLCs were selectively depleted by a single injection of clodronate laden liposomes in the knee joint seven days before induction of collagen type II arthritis (CIA). Clodronate laden liposomes were given in one knee joint either alone or in combination with a short-term oral treatment of dexamethasone. Cartilage damage including proteoglycan depletion and chondrocyte death was measured in total knee joints sections stained with safranin-o or haematoxylin. <h3>RESULTS</h3> Local removal of phagocytic SLCs, seven days before arthritis onset, prevented cell influx for the larger part. Chondrocyte death was significantly decreased in the SLC depleted arthritic joint both at an early (6 days) and late (12 days) time point after CIA induction. However, depletion of proteoglycans from femoral and patellar cartilage layers was not prevented. If the mild acute inflammation caused by a single clodronate laden liposome injection in the left knee joint, was blocked by a short-term (on consecutive days 9, 8, 7, 6, 5 before CIA onset) oral treatment with dexamethasone, cell influx, but also proteoglycan depletion was almost completely blocked. In the contralateral control right knee joint prominent cell influx and severe cartilage damage was observed, indicating that there was no effect of dexamethasone anymore at the onset of CIA. <h3>CONCLUSIONS</h3> This study shows that removal of phagocytic lining cells before CIA induction, particularly in the presence of a short-term treatment with dexamethasone, decreases cartilage destruction.
Growing consensus in asthma?
Authors: P Vermeire
Journal: European Respiratory Journal (1992)

set up by the National Heart, Lung and Blood Institute of the USA, National Institutes of Health and ably chaired by Dr AL Sheffer.It assembled eighteen recognized international experts from various countries, including twelve European colleagues with three members of our Editorial Board.The final document was officially released during the Annual Meeting of the American Academy of Allergy and Clinical Immunology in Orlando (Florida) in March 1992.Bronchial asthma is a disease with quite variable features and natural history, frequently affecting all age groups in the general population.Despite a growing awareness and interest, it remains grossly underdiagnosed and undertreated.Even after correct recognition, there used to be all but consensus on diagnostic assessment and therapeutic management.This was well demonstrated in the mid-eighties by questionnaire surveys carried out among phys icians in Europe and the USA [2, 3]; in these, considerable differences in practice were noted between participat• ing specialists in various countries and also between different specialities within countries.This was striking for important issues like the use of inhaled betaagonists, inhaled steroids and oral• theophylline for chronic maintenance therapy, or institution of irnmuno• therapy in allergic asthma.To take only one example, 92% of responding British, but only 32% and 37% of French and American respiratory specialists, respectively, claimed to be using often or always inhaled steroids as first line for chronic maintenance treatment in adults.Corresponding figures for paediatricians of these countries in children were 28, 13 and 4% respectively.Surveys among patients have confirmed these differences: whereas in a British survey in general practice 35% of 312 adult asthma patients inhaled steroids regularly [4], these drugs were virtually not used by 458 asthma patients in a rural area of France [5].The highly relevant question whether such striking differences affect outcome parameters like morbidity or mortality has not received an adequate answer, because comparative prospective studies are lacking.
A Randomized Trial of Long-Term Tinzaparin, a Low Molecular Weight Heparin (LMWH), Versus Warfarin for Treatment of Acute Venous Thromboembolism (VTE) in Cancer Patients - the CATCH Study
Authors: Agnes Y.Y. Lee, Pieter W. Kamphuisen, Guy Meyer, Rupert Bauersachs, Mette S. Janas, Mikala F Jarner, Alok A. Khorana
Journal: Blood (2014)
Anisotropy of water diffusion in the myocardium of the rat.
Authors: L Garrido, V J Wedeen, K K Kwong, U M Spencer, H L Kantor
Journal: Circulation Research (1994)

Pulsed field gradient nuclear magnetic resonance methods combined with nuclear magnetic resonance imaging were used to determine the water diffusion anisotropy in perfused rat hearts at 37 degrees C. It was found that the observed diffusion coefficient D(app) (apparent diffusion coefficient) depends on the orientation of the applied gradient g. When g is parallel to the epicardial surface, the observed diffusivity is D(app) parallel = 1.8 +/- 0.4 x 10(-9) m2.s-1, whereas when g is perpendicular to it, diffusivity is D(app) perpendicular = 2.5 +/- 0.5 x 10(-9) m2.s-1. To better characterize this directional dependence, images of the second-order diffusion tensor D of the myocardium were obtained. These data demonstrate several essential features of cardiac myoarchitecture, including the helicity of fiber orientation with respect to the ventricular axis and the variation of fiber pitch angle with transmural depth. Diffusion anisotropy may be quantified in a coordinate-independent manner by the eigenvalues of the diffusion tensor. In the myocardial midwall, these eigenvalues were E1 = 3.29 +/- 0.57, E2 = 2.01 +/- 0.42, and E3 = 0.77 +/- 0.58 x 10(-9) m2.s-1 (mean +/- SD). These data suggest that myocardial water diffusion is essentially unrestricted parallel to the myofibers. They further show that failure to measure the complete diffusion tensor may lead to substantial underestimates of diffusion anisotropy in the myocardium.
A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS
Authors: Evelyne Huynh Cong, Albane A. Bizet, Olivia Boyer, Stéphanie Woerner, Olivier Gribouval, Emilie Filhol, Christelle Arrondel, Sophie Thomas, Flora Silbermann, Guillaume Canaud, Jamil Hachicha, Nasr Ben Dhia, Marie-Noëlle Peraldi, Kais Harzallah, Daouia Iftene, Laurent Daniel, Marjolaine Willems, Laure-Hélène Noel, Christine Bole-Feysot, Patrick Nitschké, Marie-Claire Gubler, Géraldine Mollet, Sophie Saunier, Corinne Antignac
Journal: Journal of the American Society of Nephrology (2014)

Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.
Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin
Authors: Giulia Fornasa, Katerina Tsilingiri, Flavio Caprioli, Fiorenzo Botti, Marina Mapelli, Stephan Meller, Andreas Kislat, Bernhard Homey, Antonio Di Sabatino, Angelica Sonzogni, Giuseppe Viale, Giuseppe Diaferia, Alessandro Gori, Renato Longhi, Giuseppe Penna, Maria Rescigno
Journal: Journal of Allergy and Clinical Immunology (2015)

BackgroundThymic stromal lymphopoietin (TSLP) is a cytokine with pleiotropic functions in the immune system. It has been associated with allergic reactions in the skin and lungs but also homeostatic tolerogenic responses in the thymus and gut.ObjectiveIn human subjects TSLP is present in 2 isoforms, short and long. Here we wanted to investigate the differential expression of the TSLP isoforms and discern their biological implications under homeostatic or inflammatory conditions.MethodsWe evaluated the expression of TSLPs in tissues from healthy subjects, patients with ulcerative colitis, patients with celiac disease, and patients with atopic dermatitis and on epithelial cells and keratinocytes under steady-state conditions or after stimulation. We then tested the immune activity of TSLP isoforms both in vitro and in vivo.ResultsWe showed that TSLP isoforms are responsible for 2 opposite immune functions. The short isoform is expressed under steady-state conditions and exerts anti-inflammatory activities by affecting the capacity of PBMCs and dendritic cells to produce inflammatory cytokines. Moreover, the short isoform TSLP ameliorates experimental colitis in mice and prevents endotoxin shock. The long isoform of TSLP is proinflammatory and is only expressed during inflammation. The isoforms are differentially regulated by pathogenic bacteria, such as Salmonella species and adhesive-invasive Escherichia coli.ConclusionsWe have solved the dilemma of TSLP being both homeostatic and inflammatory. The TSLP isoform ratio is altered during several inflammatory disorders, with strong implications in disease treatment and prevention. Indeed, targeting of the long isoform of TSLP at the C-terminal portion, which is common to both isoforms, might lead to unwanted side effects caused by neutralization of the homeostatic short isoform.
Complications of diabetes in elderly people
Authors: E. W Gregg
Journal: BMJ (2002)

<h3>Background</h3> Although it is known that pregnancy intention impacts contraceptive use, there has been little exploration into the relationship between pregnancy intention and long-acting reversible contraception (LARC) non-use in the Australian context. <h3>Methods</h3> Semi-structured telephone interviews with a sample of participants from the Contraceptive Use, Pregnancy Intention and Decisions (CUPID) Study were conducted in 2016. <h3>Results</h3> Of the 59 women contacted, 15 participated in an interview. One theme arising from these interviews is reported here. Results from the analysis suggest that women with ambivalent or unclear plans toward pregnancy were less likely to perceive LARC as a suitable method for them. Conversely, women who clearly intended to avoid pregnancy and who had clear plans for future pregnancy valued these methods, and often framed their future plans for pregnancy within the context of their chosen LARC. <h3>Conclusions</h3> Findings presented demonstrated the complex relationship between pregnancy intention and contraceptive use. In particular, this study provided insight into the complex notion of pregnancy ambivalence. Dichotomous definitions of pregnancy as intended or unintended were found to be inadequate in encapsulating actual reproductive experiences.
<i>HLA-DQA1</i>*<i>02:01</i> Is a Major Risk Factor for Lapatinib-Induced Hepatotoxicity in Women With Advanced Breast Cancer
Authors: Colin F. Spraggs, Laura R. Budde, Linda P. Briley, Nan Bing, Charles J. Cox, Karen S. King, John C. Whittaker, Vincent E. Mooser, Alaknanda J. Preston, Steven H. Stein, Lon R. Cardon
Journal: Journal of Clinical Oncology (2011)

Purpose Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants associated with lapatinib-induced ALT elevation and hepatobiliary AEs. Patients and Methods A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT ≤ 1× ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients. Results Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases and in 21% of controls (P &lt; .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively. Conclusion These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment.
The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) Statement
Authors: Eric I. Benchimol, Liam Smeeth, Astrid Guttmann, Katie Harron, David Moher, Irene Petersen, Henrik T. Sørensen, Erik von Elm, Sinéad M. Langan
Journal: PLoS Medicine (2015)

Routinely collected health data, obtained for administrative and clinical purposes without specific a priori research goals, are increasingly used for research. The rapid evolution and availability of these data have revealed issues not addressed by existing reporting guidelines, such as Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). The REporting of studies Conducted using Observational Routinely collected health Data (RECORD) statement was created to fill these gaps. RECORD was created as an extension to the STROBE statement to address reporting items specific to observational studies using routinely collected health data. RECORD consists of a checklist of 13 items related to the title, abstract, introduction, methods, results, and discussion section of articles, and other information required for inclusion in such research reports. This document contains the checklist and explanatory and elaboration information to enhance the use of the checklist. Examples of good reporting for each RECORD checklist item are also included herein. This document, as well as the accompanying website and message board (http://www.record-statement.org), will enhance the implementation and understanding of RECORD. Through implementation of RECORD, authors, journals editors, and peer reviewers can encourage transparency of research reporting.
The PKC inhibitor AEB071 may be a therapeutic option for psoriasis
Authors: Hans Skvara, Markus Dawid, Elise Kleyn, Barbara Wolff, Josef G. Meingassner, Hilary Knight, Thomas Dumortier, Tamara Kopp, Nasanin Fallahi, Georg Stary, Christoph Burkhart, Olivier Grenet, Juergen Wagner, Youssef Hijazi, Randall E. Morris, Claire McGeown, Christiane Rordorf, Christopher E.M. Griffiths, Georg Stingl, Thomas Jung
Journal: Journal of Clinical Investigation (2008)

PKC isoforms tau, alpha, and beta play fundamental roles in the activation of T cells and other immune cell functions. Here we show that the PKC inhibitor AEB071 both abolishes the production of several cytokines by activated human T cells, keratinocytes, and macrophages in vitro and inhibits an acute allergic contact dermatitis response in rats. To translate these findings into humans, single and multiple ascending oral doses of AEB071 were administered to healthy volunteers and patients with psoriasis, respectively. AEB071 was well tolerated with no clinically relevant laboratory abnormalities. Ex vivo stimulation of lymphocytes from subjects exposed to single doses of AEB071 resulted in a dose-dependent inhibition of both lymphocyte proliferation and IL2 mRNA expression. Clinical severity of psoriasis was reduced up to 69% compared with baseline after 2 weeks of treatment, as measured by the Psoriasis Area Severity Index (PASI) score. The improvement in psoriasis patients was accompanied by histological improvement of skin lesions and may be partially explained by a substantial reduction of p40+ dermal cells, which are known to mediate psoriasis. These data suggest that AEB071 could be an effective novel treatment regimen for psoriasis and other autoimmune diseases, and that AEB071 warrants long-term studies to establish safety and efficacy.
Comparison of the antiasthmatic, oropharyngeal, and systemic glucocorticoid effects of budesonide administered through a pressurized aerosol plus spacer or the Turbuhaler dry powder inhaler☆☆☆★★★
Authors: J TOOGOOD, F WHITE, J BASKERVILLE, L FRAHER, B JENNINGS
Journal: Journal of Allergy and Clinical Immunology (1997)