tbuckley/cabot-search huggingface dataset:
Kit regulatory elements required for expression in developing hematopoietic and germ cell lineages
Authors: Linda A. Cairns, Emanuela Moroni, Elena Levantini, Alessandra Giorgetti, Francesca G. Klinger, Simona Ronzoni, Laura Tatangelo, Cecilia Tiveron, Massimo De Felici, Susanna Dolci, Maria Cristina Magli, Barbara Giglioni, Sergio Ottolenghi
Journal: Blood (2003)
The Effect of Direct Renin Inhibition Alone and in Combination With ACE Inhibition on Endothelial Function, Arterial Stiffness, and Renal Function in Type 1 Diabetes
Authors: David Z.I. Cherney, James W. Scholey, Shan Jiang, Ronnie Har, Vesta Lai, Etienne B. Sochett, Heather N. Reich
Journal: Diabetes Care (2012)

Diabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes.Arterial stiffness (augmentation index), flow-mediated vasodilatation (FMD), and renal hemodynamic function (inulin and paraaminohippurate clearance) were measured at baseline under clamped euglycemic and hyperglycemic conditions (n = 21). Measures were repeated after 4 weeks of aliskiren therapy and again after aliskiren plus ramipril.Blood pressure-lowering effects of aliskiren were similar during clamped euglycemia and hyperglycemia. Combination therapy augmented this effect under both glycemic conditions (P = 0.0005). Aliskiren reduced arterial stiffness under clamped euglycemic and hyperglycemic conditions, and the effects were augmented by dual RAS blockade (-3.4 ± 11.2 to -8.0 ± 11.5 to -14.3 ± 8.4%, respectively, during euglycemia, P = 0.0001). During clamped euglycemia, aliskiren increased FMD; dual therapy exaggerated this effect (5.1 ± 3.3 to 7.5 ± 3.0 to 10.8 ± 3.5%, repeated-measures ANOVA, P = 0.0001). Aliskiren monotherapy caused renal vasodilatation during clamped hyperglycemia only. In contrast, dual therapy augmented renal vasodilatory effects during clamped euglycemia and hyperglycemia.In patients with uncomplicated type 1 diabetes, aliskiren-based dual RAS blockade is associated with greater arterial compliance, FMD, and renal vasodilatation.
Glycosylphosphatidylinositol Anchors of<i>Plasmodium falciparum</i>
Authors: Ramachandra S. Naik, OraLee H. Branch, Amina S. Woods, Matam Vijaykumar, Douglas J. Perkins, Bernard L. Nahlen, Altaf A. Lal, Robert J. Cotter, Catherine E. Costello, Christian F. Ockenhouse, Eugene A. Davidson, D. Channe Gowda
Journal: The Journal of Experimental Medicine (2000)

Induction of proinflammatory cytokine responses by glycosylphosphatidylinositols (GPIs) of intraerythrocytic Plasmodium falciparum is believed to contribute to malaria pathogenesis. In this study, we purified the GPIs of P. falciparum to homogeneity and determined their structures by biochemical degradations and mass spectrometry. The parasite GPIs differ from those of the host in that they contain palmitic (major) and myristic (minor) acids at C-2 of inositol, predominantly C18:0 and C18:1 at sn-1 and sn-2, respectively, and do not contain additional phosphoethanolamine substitution in their core glycan structures. The purified parasite GPIs can induce tumor necrosis factor alpha release from macrophages. We also report a new finding that adults who have resistance to clinical malaria contain high levels of persistent anti-GPI antibodies, whereas susceptible children lack or have low levels of short-lived antibody response. Individuals who were not exposed to the malaria parasite completely lack anti-GPI antibodies. Absence of a persistent anti-GPI antibody response correlated with malaria-specific anemia and fever, suggesting that anti-GPI antibodies provide protection against clinical malaria. The antibodies are mainly directed against the acylated phosphoinositol portion of GPIs. These results are likely to be valuable in studies aimed at the evaluation of chemically defined structures for toxicity versus immunogenicity with implications for the development of GPI-based therapies or vaccines.
Genome-wide survey of post-meiotic segregation during yeast recombination
Authors: Eugenio Mancera, Richard Bourgon, Wolfgang Huber, Lars M Steinmetz
Journal: Genome biology (2011)

When mismatches in heteroduplex DNA formed during meiotic recombination are left unrepaired, post-meiotic segregation of the two mismatched alleles occurs during the ensuing round of mitosis. This gives rise to somatic mosaicism in multicellular organisms and leads to unexpected allelic combinations among progeny. Despite its implications for inheritance, post-meiotic segregation has been studied at only a few loci. By genotyping tens of thousands of genetic markers in yeast segregants and their clonal progeny, we analyzed post-meiotic segregation at a genome-wide scale. We show that post-meiotic segregation occurs in close to 10% of recombination events. Although the overall number of markers affected in a single meiosis is small, the rate of post-meiotic segregation is more than five orders of magnitude larger than the base substitution mutation rate. Post-meiotic segregation took place with equal relative frequency in crossovers and non-crossovers, and usually at the edges of gene conversion tracts. Furthermore, post-meiotic segregation tended to occur in markers that are isolated from other heterozygosities and preferentially at polymorphism types that are relatively uncommon in the yeast species. Overall, our survey reveals the genome-wide characteristics of post-meiotic segregation. The results show that post-meiotic segregation is widespread in meiotic recombination and could be a significant determinant of allelic inheritance and allele frequencies at the population level.
CELLULAR INTERACTIONS IN THE PROLIFERATIVE RESPONSE OF HUMAN T AND B LYMPHOCYTES TO PHYTOMITOGENS AND ALLOGENEIC LYMPHOCYTES
Authors: Hans-Peter Lohrmann, Ligita Novikovs, Robert G. Graw
Journal: The Journal of Experimental Medicine (1974)

In vitro studies were performed to determine the proliferative responsiveness of human peripheral blood thymus-dependent (T) and thymus-independent (B) lymphocytes to phytomitogens and allogeneic lymphocytes. Recombination of T and B cells, with selective inhibition of proliferation of one of the two populations, was used to identify cellular interactions which may contribute to cell proliferation. The distinctive feature of human T lymphocytes to form rosettes with unsensitized sheep erythrocytes was utilized to separate human peripheral blood lymphocytes into highly purified resetting (T) and non-rosetting (B) cells. The proliferative response of these separated lymphocyte subpopulations to various stimulants was assessed from the uptake of tritiated thymidine into DNA. Phytohemagglutinin, concanavalin A, pokeweed mitogen, and allogeneic lymphocytes stimulated separated T cells, whereas no proliferation was observed with the T-cell-depleted B-cell population. This suggests that it is the human T cell which is activated directly by these stimulants. In the presence of T cells (proliferating or nonproliferating), B cells were capable of proliferation following stimulation with phytomitogens, but not in response to histocompatibility antigens. Thus, T-cell-mediated B-cell proliferation contributes to the overall lymphocyte response in phytomitogen-stimulated T + B cell mixtures, but not in human mixed leukocyte cultures. T-cell activation by allogeneic cells required the presence of monocytes; in contrast, the three tested phytomitogens stimulated T cells in the absence of monocytes. This indicates that direct interaction of mitogens with lymphocyte membrane receptors is sufficient to trigger T cells into proliferative response. However, monocytes considerably enhanced the proliferative response of T cells in a dose-dependent fashion; this monocyte-dependent mechanism of T-cell activation was predominant at lower concentrations of phytomitogens, and contributed relatively less at higher mitogen doses. Both, the direct, monocyte-independent, and the indirect, monocyte-dependent T-lymphocyte activation contribute to the total in vitro response of lymphocyte preparations to phytomitogens.
Outcome measures for clinical trials in paediatric IBD: an evidence-based, expert-driven practical statement paper of the paediatric ECCO committee
Authors: Frank M Ruemmele, Jeffrey S Hyams, Anthony Otley, Anne Griffiths, Kaija-Leena Kolho, Jorge Amil Dias, Arie Levine, Johanna C Escher, Jan Taminiau, Gabor Veres, Jean-Frederic Colombel, Séverine Vermeire, David C Wilson, Dan Turner
Journal: Gut (2014)

Although paediatric-onset IBD is becoming more common, few medications have a registered paediatric indication. There are multiple hurdles to performing clinical trials in children, emphasising the importance of choosing an appropriate outcome measure, which can facilitate enrolment, and thereby also drug approval. The aim of this consensus statement is to highlight paediatric specific issues and key factors critical for the optimal conduct of paediatric IBD trials.The Paediatric European Crohn's and Colitis Organisation (ECCO) committee has established an international expert panel to determine the best outcome measures in paediatric IBD, following a literature search and a modified Delphi process. All recommendations were endorsed by at least 80% agreement.Recognising the importance of mucosal healing (MH), the panel defined steroid-free MH as primary outcome measure for all drugs of new category with one or two postintervention endoscopies per trial (at 8-12 weeks and/or 54 weeks). Since endoscopic evaluation is a barrier for recruitment in children, trials with medications already shown to induce MH in children or adults, could use paediatric-specific disease activity scores as primary outcome, including a modified Paediatric Crohn's Disease Activity Index in Crohn's disease and the Paediatric Ulcerative Colitis Activity Index in UC. Secondary outcomes should include safety issues, MR enterography-based damage and inflammatory scores (in Crohn's disease), faecal calprotectin, quality of life scales, and a patient-reported outcome.It is crucial to perform paediatric trials early in the development of new drugs in order to reduce off-label use of IBD medication in children. The thoughtful choice of feasible and standardised outcome measures can help move us towards this goal.
Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells
Authors: Chia-Lin Chen, Hidekazu Tsukamoto, Jian-Chang Liu, Claudine Kashiwabara, Douglas Feldman, Linda Sher, Steven Dooley, Samuel W. French, Lopa Mishra, Lydia Petrovic, Joseph H. Jeong, Keigo Machida
Journal: Journal of Clinical Investigation (2013)

Tumor-initiating stem-like cells (TICs) are resistant to chemotherapy and associated with hepatocellular carcinoma (HCC) caused by HCV and/or alcohol-related chronic liver injury. Using HCV Tg mouse models and patients with HCC, we isolated CD133(+) TICs and identified the pluripotency marker NANOG as a direct target of TLR4, which drives the tumor-initiating activity of TICs. These TLR4/NANOG-dependent TICs were defective in the TGF-β tumor suppressor pathway. Functional oncogene screening of a TIC cDNA library identified Yap1 and Igf2bp3 as NANOG-dependent genes that inactivate TGF-β signaling. Mechanistically, we determined that YAP1 mediates cytoplasmic retention of phosphorylated SMAD3 and suppresses SMAD3 phosphorylation/activation by the IGF2BP3/AKT/mTOR pathway. Silencing of both YAP1 and IGF2BP3 restored TGF-β signaling, inhibited pluripotency genes and tumorigenesis, and abrogated chemoresistance of TICs. Mice with defective TGF-β signaling (Spnb2(+/-) mice) exhibited enhanced liver TLR4 expression and developed HCC in a TLR4-dependent manner. Taken together, these results suggest that the activated TLR4/NANOG oncogenic pathway is linked to suppression of cytostatic TGF-β signaling and could potentially serve as a therapeutic target for HCV-related HCC.
Effect of Previous Benign Breast Biopsy on the Interpretive Performance of Subsequent Screening Mammography
Authors: Stephen H. Taplin, L. Abraham, B. M. Geller, B. C. Yankaskas, D. S. M. Buist, R. Smith-Bindman, C. Lehman, D. Weaver, P. A. Carney, W. E. Barlow
Journal: JNCI Journal of the National Cancer Institute (2010)

Most breast biopsies will be negative for cancer. Benign breast biopsy can cause changes in the breast tissue, but whether such changes affect the interpretive performance of future screening mammography is not known.
Clinical and ultrasonographic correlation between scapular dyskinesia and subacromial space measurement among junior elite tennis players
Authors: R T Silva, L G Hartmann, C F de Souza Laurino, J P Rocha Biló
Journal: British Journal of Sports Medicine (2008)

In this study, the hypothesis that tennis players with scapular dyskinesia present a smaller subacromial space than non-athletes was investigated. Additionally, the correlation between the size of the subacromial space and abnormalities in scapular movement during arm abduction was studied.Cross-sectional study.A total of 53 elite tennis players and 20 control participants were enrolled in the study. Participation was restricted to elite-level, junior tennis players who had no current shoulder pain or history of shoulder injuries.Each individual was examined for scapular dyskinesia by a single physician and by ultrasound, with the results analysed in a blind fashion by a single radiologist.43.4% of the tennis players and 20% of control participants presented with scapular dyskinesia. Of the 106 shoulders evaluated, 39.6% of tennis players and 10% of control participants presented with scapular dyskinesia in the clinical examination (p = 0.005). Ultrasonographic measurements demonstrated that tennis players presented statistically smaller subacromial spaces compared with control participants (p<0.001). A decrease in the subacromial space was observed in tennis players when the shoulder was raised from 0 degrees to 60 degrees of abduction; however, dyskinesia-afflicted athletes demonstrated a significantly greater decrease following this movement (19.3 vs 13.8 mm, p = 0.002).The results of this study demonstrated that tennis players with scapular dyskinesia present a smaller subacromial space than control participants. Furthermore, when the shoulder was analysed dynamically, moving from neutral abduction to 60 degrees of elevation, the tennis players with scapular dyskinesia presented a greater reduction in the subacromial space compared with unaffected athletes.
Noninvasive Detection of Coronary Artery Stenoses with Multislice Computed Tomography or Magnetic Resonance Imaging
Authors: Marc Dewey, Florian Teige, Dirk Schnapauff, Michael Laule, Adrian C. Borges, Klaus-Dieter Wernecke, Tania Schink, Gert Baumann, Wolfgang Rutsch, Patrik Rogalla, Matthias Taupitz, Bernd Hamm
Journal: Annals of Internal Medicine (2006)

Background: Multislice computed tomography (CT) and magnetic resonance imaging (MRI) are the main candidates for noninvasive coronary angiography; however, multislice CT, unlike MRI, exposes patients to radiation and an iodinated intravenous contrast agent. Objective: To compare the diagnostic accuracy of multislice CT and MRI for noninvasive detection of clinically significant coronary stenoses (≥50%). Design: Prospective intention-to-diagnose study. Setting: Single tertiary referral center, Berlin, Germany. Patients: 129 consecutive patients with suspected coronary artery disease. Interventions: Multislice CT and MRI were both performed within a median of 1 day before conventional coronary angiography, which served as the reference standard. Measurements: Diagnostic performance of multislice CT and MRI. Results: 129 patients completed the study. Altogether, 108 patients with 430 vessels could be examined with both multislice CT and MRI and were used for analysis. In the per-patient analysis, the sensitivity of multislice CT (92% [95% CI, 82% to 96%]) was significantly higher than that of MRI (74% [CI, 61% to 83%]; P = 0.013). The sensitivity for detecting clinically significant stenoses was 82% for multislice CT and 54% for MRI (P < 0.001). Specificity and negative predictive value of multislice CT and MRI in the per-vessel analysis were 90% versus 87% (P = 0.73) and 95% versus 90% (P = 0.032), respectively. The effective radiation dose used with multislice CT (mean, 12.3 mSv [SD, 1.4]) in a consecutive subgroup of 73 patients was not significantly different from that used with diagnostic cardiac catheterization (11.4 mSv [SD, 4.8]) (P = 0.169). Most patients (74%) indicated that they would prefer multislice CT for future diagnostic imaging (P < 0.001). Limitations: This was a single-center study with 129 patients. Conclusions: In patients referred for conventional coronary angiography, multislice CT compares favorably with MRI for noninvasive detection of coronary stenoses.
Guidelines for the management of vulvodynia
Authors: D. Mandal, D. Nunns, M. Byrne, J. McLelland, R. Rani, J. Cullimore, D. Bansal, F. Brackenbury, G. Kirtschig, M. Wier
Journal: British Journal of Dermatology (2010)

These guidelines for the management of vulvodynia have been prepared by the British Society for the Study of Vulval Diseases Guideline Group. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines.
Cardiovascular Biomarkers, Cardiac Dysfunction, and Outcomes in Patients With Type 2 Diabetes: A Prospective, Multicenter Study
Authors: Serge Masson, Roberto Latini, Giovanni Cioffi, Renato Urso, Tarcisio Vago, Donata Lucci, Gian Francesco Mureddu, Luigi Tarantini, Pompilio Faggiano, Daniela Girfoglio, Mario Velussi, Aldo P. Maggioni, Carlo B. Giorda, Marco Comaschi
Journal: Diabetes Care (2013)

Although diabetes is a major risk factor for ischemic heart disease or heart failure (HF), and despite the fact that echocardiography has revealed a high prevalence of left ventricular (LV) diastolic and systolic dysfunctions and hypertrophy (1–3), routine screening for cardiovascular disease using echocardiography in asymptomatic patients with type 2 diabetes is not recommended by current guidelines (4). The availability of laboratory markers of cardiovascular risk would substantially contribute to the early and simple screening of patients at increased risk of HF, allowing them to be better targeted with appropriate pharmacological therapies (5). As part of the LV Dysfunction in Diabetes (DYDA) study, we assessed the relations between different laboratory markers, including centrally assayed glycated hemoglobin (HbA1c), N-terminal probrain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), …
Comparative Analysis of Organ-Specific Autoantibodies and Celiac Disease—Associated Antibodies in Type 1 Diabetic Patients, Their First-Degree Relatives, and Healthy Control Subjects
Authors: Clemens Jaeger, Erifili Hatziagelaki, Rüdiger Petzoldt, Reinhard G. Bretzel
Journal: Diabetes Care (2001)

OBJECTIVE— In type 1 diabetes the coexistence with other endocrine diseases and organ-specific autoantibodies has been frequently reported leading to the concept of autoimmune polyendocrine syndrome (APS). In addition, an association of type 1 diabetes with celiac disease has been described. These disorders share a similar genetic background, and first-degree relatives of type 1 diabetic patients may also be affected significantly. Screening for specific antibodies allows early diagnosis of these disorders. RESEARCH DESIGN AND METHODS— In the present cross-sectional study, we analyzed sera from 197 recent-onset type 1 diabetic patients at the time of diagnosis, 882 first-degree relatives, and sera of 150 healthy control subjects for prevalence and co-occurence of the following antibodies (method):insulin autoantibodies (radioimmunoassay); GAD and IA-2 antibodies(radioligand assay); islet cell antibody, anti-adrenal cortex antibodies, and anti-gastric parietal cell antibodies (indirect immunofluorescence);anti-thyroglobulin and anti-thyroid peroxidase antibodies; and gliadin IgG/A and tissue-transglutaminase IgA (enzyme-linked immunosorbent assay). RESULTS— The overall frequency of gastric patietal cell antibodies and adrenal antibodies did not differ significantly among groups. In contrast, type 1 diabetes—associated antibodies and thyroid antibodies were significantly more frequent both in recent-onset type 1 diabetic patients and in the group of first-degree relatives (P &amp;lt;0.05). The prevalence of gliadin IgG/IgA and transglutaminase IgA was significantly higher in the group of recent-onset type 1 diabetic patients(P &amp;lt; 0.05), but the difference between first-degree relatives and control subjects did not reach statistical significance. Focusing on the coexistence of antibodies, the group of recent-onset type 1 diabetic patients presented with 27.4% of the subjects testing antibody-positive—specific for two or more of the envisaged disorders (i.e., type 1 diabetes, autoimmune thyroiditis, and celiac disease) compared with 3.1% in the group of first-degree relatives and 0 of 150 in the control population (P &amp;lt;0.05). CONCLUSIONS— We conclude that, in an active case-finding strategy, recent-onset type 1 diabetic patients should be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their first-degree relatives should include at a minimum the search for thyroid autoimmunity in addition to screening for pre—type 1 diabetes.
Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease
Authors: SuJin Hwang, Ki-Duk Song, Renaud Lesourne, Jan Lee, Julia Pinkhasov, LiQi Li, Dalal El-Khoury, Paul E. Love
Journal: The Journal of Experimental Medicine (2012)

Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR ζ chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous ζ regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability.
Culture negative cytotoxin positive stools in community acquired diarrhoea.
Authors: D Burke, B J al Jumaili, H al Mardini, C O Record
Journal: Gut (1993)

In a significant proportion of cases of community acquired diarrhoea no recognised pathogen is detected. Verocytotoxin producing Escherichia coli (VTEC) are associated with haemorrhagic colitis and the haemolytic uraemic syndrome but their role in community acquired diarrhoea is not fully understood. Using a method of toxin enhancement in mixed faecal culture, 175 stools negative on culture for recognised pathogens were tested for the presence of cytotoxin and 28% were found to be positive. Nine were neutralised by anti-VT1, 29 by anti-VT2, and eight by neither. No control stool samples yielded any cytotoxin. VTEC should be considered as a causative agent in sporadic community acquired diarrhoea.