tbuckley/cabot-search huggingface dataset:
The Epithelial Cellular Adhesion Molecule (EP-Cam) Is a Ligand for the Leukocyte-Associated Immunoglobulin-like Receptor (Lair)
Authors: Linde Meyaard, Anne-Renée van der Vuurst de Vries, Talitha de Ruiter, Lewis L. Lanier, Joseph H. Phillips, Hans Clevers
Journal: The Journal of Experimental Medicine (2001)

Human leukocyte-associated immunoglobulin-like receptor (LAIR)-1 is expressed on many cells of the immune system and is predicted to mediate inhibitory functions based on the presence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain. Although the role of LAIR-1 in the regulation of immune responses in vivo is unknown, LAIR-1 cross-linking by monoclonal antibody inhibits various immune cell functions in vitro. Here, we identify the colon carcinoma-associated epithelial cellular adhesion molecule (Ep-CAM) as a ligand for LAIR-1 and LAIR-2, a related soluble LAIR-1 family member. Ep-CAM interacts with the LAIR molecules through its first epidermal growth factor domain; Ep-CAM--specific antibodies can abrogate the binding. Intraepithelial T lymphocytes express LAIR-1 and thus may interact with Ep-CAM present on human intestinal epithelium. We propose that LAIR-1--Ep-CAM interaction may contribute to mucosal tolerance and that LAIR-2 possibly modulates this function.
Dual Inhibition of Canonical and Noncanonical NF-κB Pathways Demonstrates Significant Antitumor Activities in Multiple Myeloma
Authors: Claire Fabre, Naoya Mimura, Kathryn Bobb, Sun-Young Kong, Güllü Gorgun, Diana Cirstea, Yiguo Hu, Jiro Minami, Hiroto Ohguchi, Jie Zhang, Jeffrey Meshulam, Ruben D. Carrasco, Yu-Tzu Tai, Paul G. Richardson, Teru Hideshima, Kenneth C. Anderson
Journal: Clinical Cancer Research (2012)

NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity.Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways.We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells.Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions.
Fetal Cells Traffic to Injured Maternal Myocardium and Undergo Cardiac Differentiation
Authors: Rina J. Kara, Paola Bolli, Ioannis Karakikes, Iwao Matsunaga, Joseph Tripodi, Omar Tanweer, Perry Altman, Neil S. Shachter, Austin Nakano, Vesna Najfeld, Hina W. Chaudhry
Journal: Circulation Research (2011)

Fetal cells enter the maternal circulation during pregnancy and may persist in maternal tissue for decades as microchimeras.Based on clinical observations of peripartum cardiomyopathy patients and the high rate of recovery they experience from heart failure, our objective was to determine whether fetal cells can migrate to the maternal heart and differentiate to cardiac cells.We report that fetal cells selectively home to injured maternal hearts and undergo differentiation into diverse cardiac lineages. Using enhanced green fluorescent protein (eGFP)-tagged fetuses, we demonstrate engraftment of multipotent fetal cells in injury zones of maternal hearts. In vivo, eGFP+ fetal cells form endothelial cells, smooth muscle cells, and cardiomyocytes. In vitro, fetal cells isolated from maternal hearts recapitulate these differentiation pathways, additionally forming vascular tubes and beating cardiomyocytes in a fusion-independent manner; ≈40% of fetal cells in the maternal heart express Caudal-related homeobox2 (Cdx2), previously associated with trophoblast stem cells, thought to solely form placenta.Fetal maternal stem cell transfer appears to be a critical mechanism in the maternal response to cardiac injury. Furthermore, we have identified Cdx2 cells as a novel cell type for potential use in cardiovascular regenerative therapy.
Why does ovarian surgery in PCOS help? Insight into the endocrine implications of ovarian surgery for ovulation induction in polycystic ovary syndrome
Authors: M.L. Hendriks, J.C.F. Ket, P.G.A. Hompes, R. Homburg, C.B. Lambalk
Journal: Human Reproduction Update (2007)

Polycystic ovary syndrome (PCOS) is a complex disorder with heterogeneity of clinical and endocrine features. Ovarian surgery for ovulation induction has been used in the management of clomiphene citrate-resistant anovulatory women with PCOS. Various types of ovarian surgery have been employed (wedge resection, electrocautery, laser vaporization, multiple ovarian biopsies and others) and all procedures result in an altered endocrine profile after surgery. The mechanism behind the reversal of endocrinological dysfunction in PCOS after ovarian surgery remains incompletely understood. This review scans the literature systematically to identify the endocrine changes after ovarian surgery in PCOS, in order to glean some knowledge of the mechanism involved. After ovarian surgery in PCOS, a rapid reduction in serum levels of all ovarian hormones is seen, in combination with increased serum levels of pituitary hormones. Folliculogenesis is then initiated and ovarian hormone production increases, synchronically with a reduction of pituitary hormones. Continuation of follicle growth in subsequent cycles after ovarian surgery occurs in an environment with less androgens and lower LH and FSH levels compared with pretreatment levels. The endocrine changes found after ovarian surgery in PCOS women seem to be governed by the ovaries themselves. Rapid reduced secretion of all ovarian hormones restores feedback to the hypothalamus and pituitary, resulting in appropriate gonadotrophin secretion. Initiation of follicular development seems to be induced by increasing FSH levels following a reduction of the follicle excess and (intra-ovarian) androgen levels. Additionally, anti-Müllerian hormone and gonadotrophin surge attenuating factor probably have a role in the endocrine changes.
Anterior Insula Volume and Guilt
Authors: Andy C. Belden, Deanna M. Barch, Timothy J. Oakberg, Laura M. April, Michael P. Harms, Kelly N. Botteron, Joan L. Luby
Journal: JAMA Psychiatry (2014)

This is the first study to date to examine volumetric alterations in the anterior insula (AI) as a potential biomarker for the course of childhood major depressive disorder (MDD).To examine whether children with a history of preschool-onset (PO) MDD show reduced AI volume, whether a specific symptom of PO MDD (pathological guilt) is related to AI volume reduction (given the known relationship between AI and guilt processing), and whether AI volumes predict subsequent likelihood of having an episode of MDD.In a prospective longitudinal study, 306 children (age range, 3.00-5.11 years) and caregivers completed DSM diagnostic assessments at 6 annual time points during 10 years as part of the Preschool Depression Study. Magnetic resonance imaging was completed on a subset of 145 school-age children (age range, 6.11-12.11 years).Whole-brain-adjusted AI volume measured using magnetic resonance imaging at school age and children's diagnosis of MDD any time after their imaging.Compared with children without a history of PO MDD, school-age children previously diagnosed as having PO MDD had smaller left and right AI volumes (Wilks Λ = 0.94, F2,124 = 3.37, P = .04, Cohen d = 0.23). However, the effect of PO MDD on reduced AI volumes was better explained by children's experience of pathological guilt during preschool (Λ = 0.91, F2,120 = 6.17, P = .003, d = .30). When covarying for children's lifetime history of MDD episodes, their experience of pathological guilt during preschool, as well as their sex and age at the time of imaging, schoolchildren's right-side AI volume was a significant predictor of being diagnosed as having an MDD episode after imaging (odds ratio, 0.96; 95% CI, 0.01-0.75; P = .03).These results provide evidence that structural abnormalities in AI volume are related to the neurobiology of depressive disorders starting in early childhood. The present findings are consistent with mounting research in adult MDD suggesting that insula function and structure may be a target biomarker for major depression.
Antibody-Mediated Imbalance of Myocardial Energy Metabolism
Authors: Heinz-Peter Schultheiß, Karsten Schulze, Rolf Schauer, Bernhard Witzenbichler, Bodo Eckehard Strauer
Journal: Circulation Research (1995)

Abstract The ADP-ATP carrier of the inner mitochondrial membrane is an autoantigen in myocarditis and dilated cardiomyopathy. Sera of patients with these diseases contain carrier-specific autoantibodies that inhibit the transmembrane nucleotide transport on isolated mitochondria. Guinea pigs immunized with the isolated ADP-ATP carrier protein also generate specific carrier-inactivating antibodies. In this study, we measured the cardiac function of guinea pigs immunized with the ADP-ATP carrier by determining the external heart work (EHW) of their isolated perfused spontaneously beating hearts stimulated by 4.0 mmol/L calcium and aortic ligature. Further, the electrogenic transport activity of the ADP-ATP carrier was estimated by calculating the cytosolic-mitochondrial difference of the phosphorylation potential of ATP [ΔG(cyt-mit)] in the freeze-clamped isolated hearts by nonaqueous fractionation. The EHW of immunized guinea pigs was seen to be reduced by 54% ( P &lt;.005) compared with nonimmunized control guinea pigs, and ΔG(cyt-mit) declined from 4.9 kJ/mol ATP in nonimmunized control hearts to 2.3 kJ/mol ATP in the hearts of the immunized guinea pigs ( P &lt;.005). The decisive result of this study, however, is the close relation observed between the magnitude of reduction of ΔG(cyt-mit) and the size of the decrease in EHW ( r =.87). Therefore, it seems plausible that antibody-mediated carrier dysfunction (creating the observed imbalance in myocardial energy metabolism) is responsible for the impairment of cardiac function. Our data support the hypothesis that immunopathic mechanisms in myocarditis and dilated cardiomyopathy can trigger subsequent heart failure. The underlying pathophysiological reason seems to be a metabolic disorder initiated by the antibody-mediated inactivation of the ADP-ATP carrier.
Genetic evidence that HNF-1α–dependent transcriptional control of HNF-4α is essential for human pancreatic β cell function
Authors: Sara K. Hansen, Marcelina Párrizas, Maria L. Jensen, Stepanka Pruhova, Jakob Ek, Sylvia F. Boj, Anders Johansen, Miguel A. Maestro, Francisca Rivera, Hans Eiberg, Michal Andel, Jan Lebl, Oluf Pedersen, Jorge Ferrer, Torben Hansen
Journal: Journal of Clinical Investigation (2002)

Mutations in the genes encoding hepatocyte nuclear factor 4alpha (HNF-4alpha) and HNF-1alpha impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4alpha is known to be an essential positive regulator of HNF-1alpha. More recent data demonstrates that HNF-4alpha expression is dependent on HNF-1alpha in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1alpha to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4alpha promoter (P1). Here we report that the expression of HNF-4alpha in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G --> A mutation in a conserved nucleotide position of the HNF-1alpha binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1alpha, and consequently in reduced HNF-1alpha-dependent activation. These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.
miR-21-3p regulates cardiac hypertrophic response by targeting histone deacetylase-8
Authors: Mengwen Yan, Chen Chen, Wei Gong, Zhongwei Yin, Ling Zhou, Sandip Chaugai, Dao Wen Wang
Journal: Cardiovascular Research (2014)

Growing evidences indicate that microRNAs (miRNAs) are involved in cardiac hypertrophy development. Multiple miRNAs have been identified as diagnostic and prognostic biomarkers of cardiac hypertrophy, as well as potential therapeutic tools. The present study aimed to investigate the functions and regulatory mechanisms of miR-21-3p in cardiac hypertrophy.Decreased expression of miR-21-3p was observed in cardiac hypertrophy induced by transverse aortic constriction (TAC) and angiotensin (Ang) II infusion in mice. To further explore the role of miR-21-3p in cardiac hypertrophy, rAAV-miR-21-3p was administered intravenously in mice. Overexpression of miR-21-3p markedly suppressed TAC-induced cardiac hypertrophy and also blocked Ang II-induced cardiac hypertrophy as determined by cardiac function measurement and biomarker detection. Furthermore, western blot assays showed that histone deacetylase-8 (HDAC8) was silenced by miR-21-3p, and luciferase reporter assays showed that miR-21-3p binds to the 3' UTR of HDAC8. Moreover, re-expression of HDAC8 attenuated miR-21-3p-mediated suppression of cardiac hypertrophy by enhancing phospho-Akt and phospho-Gsk3β expression.Our data reveal a role of miR-21-3p in regulating HDAC8 expression and Akt/Gsk3β pathway, and suggest that modulation of miR-21-3p levels may provide a therapeutic approach for cardiac hypertrophy.
Phase II Study of Pemetrexed-Gemcitabine Combination in Patients with Advanced-Stage Non-Small Cell Lung Cancer
Authors: Christian Monnerat, Thierry Le Chevalier, Karen Kelly, Coleman K. Obasaju, Julie Brahmer, Silvia Novello, Takashi Nakamura, Astra M. Liepa, Laurence Bozec, Paul A. Bunn, David S. Ettinger
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Cisplatin is one of the most active agents for the treatment of non-small cell lung cancer (NSCLC). It is also known for significant toxicity, which makes it unsuitable for certain patients. Our purpose was to evaluate the efficacy and toxicity of a promising cisplatin-free combination, gemcitabine plus pemetrexed, in NSCLC. Experimental Design: Chemo-naive patients with inoperable NSCLC were eligible for this study. Gemcitabine (1250 mg/m2) was given intravenously on days 1 and 8, followed by intravenous pemetrexed (500 mg/m2) on day 8. After inclusion of 13 patients, folic acid and vitamin B12 supplementation was added to lower pemetrexed-induced toxicity. Quality of life was assessed with the Lung Cancer Symptom Scale. Results: Sixty patients enrolled; 58 were evaluable for response. All patients had a World Health Organization performance status of 0 or 1. Eighty-seven percent had stage IV disease. Nine patients had a confirmed partial response [overall response rate, 15.5%; 95% confidence interval (CI), 7.3–27.4%]. Twenty-nine (50.0%) patients had stable disease. Median overall survival was 10.1 months (95% CI, 7.9–13.0 months), with a 1- and 2-year overall survival of 42.6% (95% CI, 30.0–55.3%) and 18.5% (95% CI, 7.9–29.1%). Median progression-free survival was 5.0 months. Median response duration was 3.3 months. There were no deaths attributed to treatment. Common Toxicity Criteria grade 3/4 toxicities were neutropenia (61.7%), febrile neutropenia (16.7%), fatigue (23.3%), and elevations of aspartate aminotransferase (15.0%) and alanine aminotransferase (20.0%). Conclusions: This combination had good tolerance and achieved promising overall survival with extended 1- and 2-year survival rates. This cisplatin-free regimen warrants further evaluation in randomized trials.
Doctors and overpopulation.
Authors: G Morris
Journal: BMJ (1973)

severe pre-eclampsia may occur early enough to retard fetal growth.It is therefore im- portant to distinguish between pre-eclawpsia and eclampsia in such comparisons.The relatively small percentage of Yoruba primigravidae who are over 25 years of age tend to be overweight and to show a higher than average incidence of pre-eclampsia during pregnancy of the type seen in Europe.These women are usually in non- manual occupations.There is good evidence that hy,pertension is common in Yoruba women in middle life.-I am, etc.,
Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis
Authors: Martina Korfei, Sylwia Skwarna, Ingrid Henneke, BreAnne MacKenzie, Oleksiy Klymenko, Shigeki Saito, Clemens Ruppert, Daniel von der Beck, Poornima Mahavadi, Walter Klepetko, Saverio Bellusci, Bruno Crestani, Soni Savai Pullamsetti, Ludger Fink, Werner Seeger, Oliver Holger Krämer, Andreas Guenther
Journal: Thorax (2015)

<h3>Background</h3> Activation and differentiation of fibroblasts into contractile protein-expressing myofibroblasts and their acquired apoptosis-resistant phenotype are critical factors towards the development of idiopathic pulmonary fibrosis (IPF), a fatal disease characterised by distorted pulmonary structure and excessive extracellular matrix (ECM) deposition. The molecular mechanisms underlying these processes in IPF remain incompletely understood. We investigated the possible implication of aberrant overexpression and activity of histone deacetylases (HDACs) in IPF. <h3>Methods</h3> We analysed lung tissues from patients with sporadic IPF (n=26) and non-diseased control lungs (n=16) for expression of class I and II HDACs. Primary IPF fibroblasts were treated with HDAC inhibitors (HDACi) LBH589 or valproic acid (VPA). <h3>Results</h3> Compared to control lungs, protein levels of class I (HDAC1, HDAC2, HDAC3, HDAC8) and class II HDACs (HDAC4, HDAC 5, HDAC 7, HDAC 9) were significantly elevated in IPF lungs. Using immunohistochemistry, strong induction of nearly all HDAC enzymes was observed in myofibroblasts of fibroblast foci and in abnormal bronchiolar basal cells at sites of aberrant re-epithelialisation in IPF lungs, but not in controls. Treatment of primary IPF fibroblasts with the pan-HDACi LBH589 resulted in significantly reduced expression of genes associated with ECM synthesis, proliferation and cell survival, as well as in suppression of HDAC7, and was paralleled by induction of endoplasmic reticulum stress and apoptosis. The profibrotic and apoptosis-resistant phenotype of IPF fibroblasts was also partly attenuated by the class I HDACi VPA. <h3>Conclusions</h3> Aberrant overexpression of HDACs in basal cells of IPF lungs may contribute to the bronchiolisation process in this disease. Similarly, generation and apoptosis resistance of IPF fibroblasts are mediated by enhanced activity of HDAC enzymes. Therefore, pan-HDAC inhibition by LBH589 may present a novel therapeutic option for patients with IPF.
Identification of signaling components required for the prediction of cytokine release in RAW 264.7 macrophages.
Authors: Sylvain Pradervand, Mano R Maurya, Shankar Subramaniam
Journal: Genome biology (2006)

Abstract Background Release of immuno-regulatory cytokines and chemokines during inflammatory response is mediated by a complex signaling network. Multiple stimuli produce different signals that generate different cytokine responses. Current knowledge does not provide a complete picture of these signaling pathways. However, using specific markers of signaling pathways, such as signaling proteins, it is possible to develop a 'coarse-grained network' map that can help understand common regulatory modules for various cytokine responses and help differentiate between the causes of their release. Results Using a systematic profiling of signaling responses and cytokine release in RAW 264.7 macrophages made available by the Alliance for Cellular Signaling, an analysis strategy is presented that integrates principal component regression and exhaustive search-based model reduction to identify required signaling factors necessary and sufficient to predict the release of seven cytokines (G-CSF, IL-1α, IL-6, IL-10, MIP-1α, RANTES, and TNFα) in response to selected ligands. This study provides a model-based quantitative estimate of cytokine release and identifies ten signaling components involved in cytokine production. The models identified capture many of the known signaling pathways involved in cytokine release and predict potentially important novel signaling components, like p38 MAPK for G-CSF release, IFNγ- and IL-4-specific pathways for IL-1a release, and an M-CSF-specific pathway for TNFα release. Conclusion Using an integrative approach, we have identified the pathways responsible for the differential regulation of cytokine release in RAW 264.7 macrophages. Our results demonstrate the power of using heterogeneous cellular data to qualitatively and quantitatively map intermediate cellular phenotypes.
Evaluation of a Qualitative Precipitation Reaction for the Detection of the Rheumatoid Factor
Authors: Wallace V. Epstein, Ephraim P. Engleman, Margaret Ross
Journal: Annals of the Rheumatic Diseases (1957)

FromtheRheumatic Disease Group oftheDepartment ofMedicine, andtheMetabolic UnitforResearch in Arthritis andAllied Diseases, University ofCalifornia School ofMedicine, SanFrancisco, California Thetermrheumatoid factor (R.F.) hasbeen applied tothesubstance orsubstances intheserum ofmostindividuals havingrheumatoid arthritis which combines with immuneglobulins orsubstances closely associated withimmuneglobulins. Theterm  refers tothefactthatitismost frequently detected intheserumofindividuals having rheumatoid arthritis; itisalsofoundin aboutonethird toonehalfofpatients withdisseminated lupus erythematosus andinsomesera frompatients withother connective tissue diseases
Revascularization Versus Implantable Cardioverter-Defibrillators to Prevent Sudden Death in Patients With Severe Left Ventricular Dysfunction
Authors: William S. Weintraub
Journal: Circulation (2001)

udden death remains a dreaded consequence of coronary artery disease, and efforts to predict its incidence and to prevent its occurrence remain a major concern.A number of the challenges in management are highlighted in the article by Veenhuyzen et al 1 in the present issue of Circulation.In their study, mortality and modes of death were assessed in 5410 patients with ischemic left ventricular function who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) study. 2 There were 1870 patients who had had prior coronary artery bypass grafting (CABG) and 3540 who had not had prior CABG.The SOLVD trial database is a good source for these data, both because it is large and because the cause of death (ie, whether cardiac and whether sudden or not) was established.