tbuckley/cabot-search huggingface dataset:
A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate–mediated egress
Authors: César Nombela-Arrieta, Thorsten R. Mempel, Silvia F. Soriano, Irina Mazo, Matthias P. Wymann, Emilio Hirsch, Carlos Martínez-A., Yoshinori Fukui, Ulrich H. von Andrian, Jens V. Stein
Journal: The Journal of Experimental Medicine (2007)

Recent observations using multiphoton intravital microscopy (MP-IVM) have uncovered an unexpectedly high lymphocyte motility within peripheral lymph nodes (PLNs). Lymphocyte-expressed intracellular signaling molecules governing interstitial movement remain largely unknown. Here, we used MP-IVM of murine PLNs to examine interstitial motility of lymphocytes lacking the Rac guanine exchange factor DOCK2 and phosphoinositide-3-kinase (PI3K)γ, signaling molecules that act downstream of G protein–coupled receptors, including chemokine receptors (CKRs). T and B cells lacking DOCK2 alone or DOCK2 and PI3Kγ displayed markedly reduced motility inside T cell area and B cell follicle, respectively. Lack of PI3Kγ alone had no effect on migration velocity but resulted in increased turning angles of T cells. As lymphocyte egress from PLNs requires the sphingosine-1-phosphate (S1P) receptor 1, a Gαi protein–coupled receptor similar to CKR, we further analyzed whether DOCK2 and PI3Kγ contributed to S1P-triggered signaling events. S1P-induced cell migration was significantly reduced in T and B cells lacking DOCK2, whereas T cell–expressed PI3Kγ contributed to F-actin polymerization and protein kinase B phosphorylation but not migration. These findings correlated with delayed lymphocyte egress from PLNs in the absence of DOCK2 but not PI3Kγ, and a markedly reduced cell motility of DOCK2-deficient T cells in close proximity to efferent lymphatic vessels. In summary, our data support a central role for DOCK2, and to a lesser extent T cell–expressed PI3Kγ, for signal transduction during interstitial lymphocyte migration and S1P-mediated egress.
Telomerase Repressor Sequences on Chromosome 3 and Induction of Permanent Growth Arrest in Human Breast Cancer Cells
Authors: A. P. Cuthbert, J. Bond, D. A. Trott, S. Gill, J. Broni, A. Marriott, G. Khoudoli, E. K. Parkinson, C. S. Cooper, R. F. Newbold
Journal: JNCI Journal of the National Cancer Institute (1999)

Activation of the enzyme telomerase, which has been associated with cellular immortality, may constitute a key step in the development of human cancer. Telomerase is repressed in most normal human somatic cells. This study was conducted, using a genetic complementation approach, with the aim of identifying and mapping the genes responsible for repressing telomerase and, simultaneously, to establish the effect of experimentally induced telomerase repression on human tumor cell growth.Individual human chromosomes isolated from normal diploid cells and tagged with bacterial antibiotic resistance genes (for later selection) were introduced into cells of the human breast carcinoma cell line 21NT by means of microcell transfer. Selected hybrid clones were screened for telomerase activity by use of the polymerase chain reaction-based telomere repeat amplification protocol (TRAP) assay, and the proliferative fate of the hybrid clones was determined. Regions of the introduced chromosomes associated with telomerase repression were mapped using segregant hybrids and a deletion analysis that employed microsatellite DNA markers.Strong repression of telomerase was observed following transfer of human chromosome 3 into 21NT cells but not after transfer of chromosomes 8, 12, or 20. The vast majority of hybrid clones with repressed telomerase entered permanent growth arrest after 10-18 population doublings. Deletion analysis of nonrepressed segregant monochromosome 3 hybrids indicated two regions on the short arm of chromosome 3 (3p21.3-p22 and 3p12-21.1) where telomerase regulator genes may be located.Telomerase in human breast cancer cells is efficiently repressed by a gene or genes on normal human chromosome 3p, and this repression is associated with permanent growth arrest of the tumor cells.
Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis
Authors: B Hoppe, T Haupl, K Egerer, R Gruber, H Kiesewetter, A Salama, G R Burmester, T Dorner
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Background:</h3> Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anti-cyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting the course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, both of which have been implicated in anti-CCP generation, are assumed to be associated with RA. <h3>Objectives:</h3> To elucidate whether PADI4 affects the clinical characteristics of RA, and whether it would modulate the effect of anti-CCPs on clinical course. The combined effect of SE and PADI4 on autoantibody profile was also analysed. <h3>Methods:</h3> 373 patients with RA were studied. SE, padi4_94C&gt;T, rheumatoid factor, anti-CCPs and antinuclear antibodies (ANAs) were determined. Disease severity was characterised by cumulative therapy intensity classified into ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score. <h3>Results:</h3> CTI was significantly associated with disease duration, erosive disease, disease activity score (DAS) 28 and anti-CCPs. The association of anti-CCPs with CTI was considerably influenced by padi4_94C&gt;T genotype (C/C: OR<sub>adj</sub> = 0.93, p<sub>adj</sub> = 0.92; C/T: OR<sub>adj</sub> = 2.92, p<sub>adj</sub> = 0.093; T/T: OR<sub>adj</sub> = 15.3, p<sub>adj</sub> = 0.002). Carriage of padi4_94T exhibited a significant trend towards higher Steinbrocker scores in univariate and multivariate analyses. An association of padi4_94C&gt;T with ANAs was observed, with noteworthy differences depending on SE status (SE−: OR<sub>adj</sub> = 6.20, p<sub>adj</sub>&lt;0.04; SE+: OR<sub>adj</sub> = 0.36, p<sub>adj</sub> = 0.02) and significant heterogeneity between the two SE strata (p = 0.006). <h3>Conclusions:</h3> PADI4 genotype in combination with anti-CCPs and SE modulates clinical and serological characteristics of RA.
(8) Extramammary Paget's disease
Authors: MAUREEN WALSH, J.E. SOMER VILLE, J.R. CORBETT
Journal: British Journal of Dermatology (1992)

Journal Article (8) Extramammary Paget's disease Get access MAUREEN WALSH, MAUREEN WALSH Departments of Pathology, Royal Victoria Hospital, Belfast, U.K. Search for other works by this author on: Oxford Academic Google Scholar J.E. SOMER VILLE, J.E. SOMER VILLE Departments of Pathology, Royal Victoria Hospital, Belfast, U.K. Search for other works by this author on: Oxford Academic Google Scholar J.R. CORBETT J.R. CORBETT Departments of Dermatology, Royal Victoria Hospital, Belfast, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 127, Issue s40, 1 July 1992, Page 42, https://doi.org/10.1111/j.1365-2133.1992.tb01222.x Published: 01 July 1992
Levels of Homology and the Problem of Neocortex
Authors: Jennifer Dugas-Ford, Clifton W. Ragsdale
Journal: Annual Review of Neuroscience (2015)

The neocortex is found only in mammals, and the fossil record is silent on how this soft tissue evolved. Understanding neocortex evolution thus devolves to a search for candidate homologous neocortex traits in the extant nonmammalian amniotes. The difficulty is that homology is based on similarity, and the six-layered neocortex structure could hardly be more dissimilar in appearance from the nuclear organization that is so conspicuous in the dorsal telencephalon of birds and other reptiles. Recent molecular data have, however, provided new support for one prominent hypothesis, based on neuronal circuits, that proposes the principal neocortical input and output cell types are a conserved feature of amniote dorsal telencephalon. Many puzzles remain, the greatest being understanding the selective pressures and molecular mechanisms that underlie such tremendous morphological variation in telencephalon structure.
The stars within the melanocytic garden: unusual variants of Spitz naevi
Authors: E. Moscarella, S. Al Jalbout, S. Piana, G. Argenziano, A. Lallas, C. Longo, R. Hofmann-Wellenhof, I. Zalaudek
Journal: British Journal of Dermatology (2014)

Spitz naevi may present a wide spectrum of morphologies. Histopathologically, many variants, including desmoplastic, angiomatoid, verrucous/polypoid, plexiform, pagetoid, halo, myxoid, granulomatous and tubular Spitz naevi have been described. Clinical and dermoscopic features of these unusual variants of Spitz naevi have been reported only rarely. The aim of this study is to describe clinical, dermoscopic and histopathological features of uncommon morphological variants of Spitz naevi in order to raise awareness among clinicians about their peculiar patterns of presentation. We searched our image database retrospectively from 2004 to 2014 for images of excised tumours using Spitz/Reed naevus as a keyword. A total of 307 excised skin lesions with a histopathological diagnosis of Spitz/Reed naevus were found. Among those we identified 13 uncommon variants of Spitz naevi including six cases of desmoplastic Spitz naevus, five cases of angiomatoid Spitz naevus and two cases of verrucous Spitz naevus. These lesions did not fulfil the already described dermoscopic criteria of Spitz naevi, with the exception of angiomatoid Spitz naevi, exhibiting a pinkish background and dotted vessels in dermoscopy. Desmoplastic Spitz naevi may be difficult to differentiate from dermatofibroma clinically, and from melanoma under dermoscopic examination. Verrucous Spitz naevi, despite their relatively unusual clinical features, show reassuring morphological clues histologically, which allows the differential diagnosis from an atypical spitzoid tumour. In all cases an atypical melanocytic lesion could not be excluded under dermoscopy, thus warranting excision and histopathological examination.
Providing preventive care to migrants saves money, study finds
Authors: Anne Gulland
Journal: BMJ (2015)

Providing migrants with access to preventive treatment rather than waiting until they need emergency care would generate cost savings, a study has found.

As the question of how many migrants Europe can take reaches the top of the political agenda, researchers at the European Union Agency for Fundamental Rights looked at the costs of providing antenatal care and hypertensive care to irregular migrants—that is, those who do not have full legal status—in Germany, Greece, and Sweden.1

Researchers used …
Predictive Value of Silent Myocardial Ischemia for Cardiac Events in Diabetic Patients
Authors: Paul Valensi, Jacques Pariès, Valérie Brulport-Cerisier, Florence Torremocha, Régis-Nessim Sachs, Gérald Vanzetto, Emmanuel Cosson, Boris Lormeau, Jean-Raymond Attali, Richard Maréchaud, Bruno Estour, Serge Halimi
Journal: Diabetes Care (2005)

Silent myocardial ischemia (SMI) in asymptomatic subjects with no history of myocardial infarction or angina is a frequent condition in diabetic patients. The aim of the study was to examine the predictive value of SMI for cardiac events in a multicenter cohort and to determine whether this value is higher in patients with a particular clinical profile.A total of 370 asymptomatic diabetic patients with at least two additional cardiovascular risk factors was recruited in four departments of diabetology. SMI was assessed by either exercise or dipyridamole single-photon emission-computed tomography myocardial perfusion imaging with thallium-201. If dipyridamole stress was used, an electrocardiogram stress test was performed separately on another day. Follow-up duration was 3-89 months (38 +/- 23 months).There was evidence of SMI in 131 patients (35.4%) on at least one positive noninvasive test. The patients with SMI were significantly older and had significantly higher serum triglycerides and lower HDL cholesterol levels. Cardiac events occurred in 53 patients (14.3%). Major cardiac events (death or myocardial infarction) occurred in 38 patients (10%) and other events (unstable angina, heart failure, or coronary revascularization) occurred in 15 patients. The patients who had cardiac events were older and had higher serum triglyceride levels at baseline. There was a significant association between SMI and cardiac events (hazard ratio 2.79 [95% CI 1.54-5.04]) and in particular major cardiac events (3 [1.53-5.87]). In the patients >60 years of age, the prevalence of SMI was higher (43.4 vs. 30.2% in those <60 years). SMI was associated with a significant risk of cardiac events (2.89 [1.31-6.39]) and in particular major cardiac events (3.66 [1.36-9.87]) for the patients >60 years old but not for those <60 years old.In asymptomatic diabetic patients with additional cardiovascular risk factors, SMI is a potent predictor of cardiac events and should be assessed preferably in the patients >60 years of age.
Serum Osteoprotegerin Levels Are Associated With the Presence and Severity of Coronary Artery Disease
Authors: Shuichi Jono, Yuji Ikari, Atsushi Shioi, Katsuhito Mori, Takami Miki, Kazuhiro Hara, Yoshiki Nishizawa
Journal: Circulation (2002)

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD).Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was a significant increase in serum OPG levels. Serum OPG levels were 0.94+/-0.34, 1.04+/-0.38, 1.19+/-0.38, and 1.44+/-0.54 ng/mL (medians 0.91, 0.99, 1.09, and 1.37) for the subjects with normal coronary arteries or luminal irregularities, 1-vessel disease, 2-vessel disease, and 3-vessel disease, respectively. Multivariate logistic regression analysis revealed that serum OPG levels were significantly associated with the presence of CAD [odds ratio, 5.2; 95% confidence interval, 1.7 to 16.0].Our data show that serum OPG levels are associated with the presence and severity of CAD, suggesting that OPG may be involved in the progression of CAD.
Crystal Structure of HLA-DR2 (DRA*0101, DRB1*1501) Complexed with a Peptide from Human Myelin Basic Protein
Authors: Kathrine J. Smith, Jason Pyrdol, Laurent Gauthier, Don C. Wiley, Kai W. Wucherpfennig
Journal: The Journal of Experimental Medicine (1998)

Susceptibility to multiple sclerosis is associated with the human histocompatibility leukocyte antigen (HLA)-DR2 (DRB1*1501) haplotype. The structure of HLA-DR2 was determined with a bound peptide from human myelin basic protein (MBP) that is immunodominant for human MBP-specific T cells. Residues of MBP peptide that are important for T cell receptor recognition are prominent, solvent exposed residues in the crystal structure. A distinguishing feature of the HLA-DR2 peptide binding site is a large, primarily hydrophobic P4 pocket that accommodates a phenylalanine of the MBP peptide. The necessary space for this aromatic side chain is created by an alanine at the polymorphic DRβ 71 position. These features make the P4 pocket of HLA-DR2 distinct from DR molecules associated with other autoimmune diseases.
Two-Dimensional Transcriptome Profiling: Identification of Messenger RNA Isoform Signatures in Prostate Cancer from Archived Paraffin-Embedded Cancer Specimens
Authors: Hai-Ri Li, Jessica Wang-Rodriguez, T. Murlidharan Nair, Joanne M. Yeakley, Young-Soo Kwon, Marina Bibikova, Christina Zheng, Lixin Zhou, Kui Zhang, Tracy Downs, Xiang-Dong Fu, Jian-Bing Fan
Journal: Cancer Research (2006)

Abstract The expression of specific mRNA isoforms may uniquely reflect the biological state of a cell because it reflects the integrated outcome of both transcriptional and posttranscriptional regulation. In this study, we constructed a splicing array to examine ∼1,500 mRNA isoforms from a panel of genes previously implicated in prostate cancer and identified a large number of cell type–specific mRNA isoforms. We also developed a novel “two-dimensional” profiling strategy to simultaneously quantify changes in splicing and transcript abundance; the results revealed extensive covariation between transcription and splicing in prostate cancer cells. Taking advantage of the ability of our technology to analyze RNA from formalin-fixed, paraffin-embedded tissues, we derived a specific set of mRNA isoform biomarkers for prostate cancer using independent panels of tissue samples for feature selection and cross-analysis. A number of cancer-specific splicing switch events were further validated by laser capture microdissection. Quantitative changes in transcription/RNA stability and qualitative differences in splicing ratio may thus be combined to characterize tumorigenic programs and signature mRNA isoforms may serve as unique biomarkers for tumor diagnosis and prognosis. (Cancer Res 2006; 66(8): 4079-88)
Variable presentation of Brugada syndrome: lessons from three generations with syncope
Authors: A. Plunkett
Journal: BMJ (2003)

General practitioners see many patients with syncope but in only a few cases is this due to a primary cardiac arrhythmia. Nevertheless, identifying such patients is important because some familial arrhythmias are associated with a risk of sudden death. We describe how a recently defined arrhythmia, Brugada syndrome, caused syncope in three generations of one family. The cases show the importance of taking an adequate family history when assessing patients with syncope and how this information is crucial to diagnosis and management.

Brugada syndrome is an inherited cardiac disease causing ventricular tachyarrhythmias in patients with structurally normal hearts.1 Since its first description in 1992, the number of cases reported worldwide has grown substantially, and it is thought to account for many cases of unexpected sudden death.

The syndrome is characterised by a history of syncope or cardiac arrest and a characteristic electrocardiographic pattern: right bundle branch block and ST segment elevation in V1 to V3. Most cases are inherited as an autosomal dominant trait, explaining a strong family history of syncope or sudden death.2 Some patients have normal resting electrocardiographic appearances but the classic changes can be induced by giving ajmaline, an antiarrhythmic drug.3

A 27 year old woman presented with three episodes of sudden loss of consciousness over six weeks. She had no palpitations and no consistent precipitants. On each occasion she was unconscious for a few seconds …
Selective Depletion of CD4+CD25+Foxp3+ Regulatory T Cells by Low-Dose Cyclophosphamide Is Explained by Reduced Intracellular ATP Levels
Authors: Jie Zhao, Yuchun Cao, Zhang Lei, Zhuoshun Yang, Biao Zhang, Bo Huang
Journal: Cancer Research (2010)

CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells have been shown to play important roles in mediating cancer development. Although cyclophosphamide (CY) has shown promise as a drug to selectively target Treg cells with low-dose in vivo, the underlying molecular mechanism remains unclear. In this report, we provide evidence that ATP, the energy molecule and signal element, accounts for the selective depletion of Treg cells by low-dose CY. Relative to conventional T cells or other cell types, ATP levels were much lower in Treg cells. This was due to Treg cells that downregulate one microRNA, miR-142-3p, and upregulate ecto-nucleoside triphosphate diphosphohydrolase CD39. The transfection of miR-142-3p or the blockade of CD39 could increase intracellular ATP levels of Treg cells, consequently decreasing the sensitivity of Treg cells to low-dose CY. On the other hand, the transfection of miR-142-3p inhibitor or the addition of soluble CD39 to the cultured CD4(+)CD25(-) T cells resulted in the decrease of intracellular ATP levels and increase of sensitivity of conventional T cells to low-dose CY. Furthermore, we found that the low levels of ATP attenuated the synthesis of glutathione, leading to the decrease of CY detoxification, thus increasing the sensitivity of Treg cells to low-dose CY. Therefore, we here identify a molecular pathway through which low-dose CY selectively ablates Treg cells. Our findings also imply that low levels of ATP are probably related to Treg cell function.
Anti–Proline-Glycine-Proline or Antielastin Autoantibodies Are Not Evident in Chronic Inflammatory Lung Disease
Authors: Catherine M. Greene, Teck Boon Low, Shane J. O'Neill, Noel G. McElvaney
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: In patients with chronic inflammatory lung disease, pulmonary proteases can generate neoantigens from elastin and collagen with the potential to fuel autoreactive immune responses. Antielastin peptide antibodies have been implicated in the pathogenesis of tobacco-smoke–induced emphysema. Collagen-derived peptides may also play a role.Objectives: To determine whether autoantibodies directed against elastin- and collagen-derived peptides are present in plasma from three groups of patients with chronic inflammatory lung disease compared with a nonsmoking healthy control group and to identify whether autoimmune responses to these peptides may be an important component of the disease process in these patients.Methods: A total of 124 patients or healthy control subjects were recruited for the study (Z-A1AT deficiency, n = 20; cystic fibrosis, n = 40; chronic obstructive pulmonary disease, n = 31; healthy control, n = 33). C-reactive protein, IL-32, and antinuclear antibodies were quantified. Antielastin and anti–N-acetylated-proline-glycine-proline autoantibodies were measured by reverse ELISA.Measurements and Main Results: All patients were deemed stable and noninfective on the basis of the absence of clinical or radiographic evidence of recent infection. There were no significant differences in the levels of autoantibodies or IL-32 in the patients groups compared with the healthy control subjects.Conclusions: Antielastin or anti–N-acetylated proline-glycine-proline autoantibodies are not evident in chronic inflammatory lung disease.