tbuckley/cabot-search huggingface dataset:
B Cell Differentiation and Immunoregulatory T Cell Function in Human Cord Blood Lymphocytes
Authors: Giovanna Tosato, Ian T. Magrath, Irma R. Koski, Nancy J. Dooley, R. Michael Blaese
Journal: Journal of Clinical Investigation (1980)

The functional maturity of T and B lymphocyte populations from human newborns was evaluated using a reverse hemolytic plaque assay to detect immunoglobulin-secreting cells generated in in vitro cultures stimulated with pokeweed mitogen (PWM), a T cell-dependent polyclonal activator, and the Epstein-Barr virus (EBV), a T cell-independent B cell activator. Cord blood lymphocytes failed to produce immunoglobulin in response to PWM, but did respond with immunoglobulin synthesis to stimulation with EBV. Co-culture experiments demonstrated that cord blood T cells would inhibit immunoglobulin production by adult cells stimulated with PWM, but not with EBV. Cord blood T cells did suppress immunoglobulin production by cord blood B cells when stimulated with a mixture of EBV and PWM, indicating that cord blood, in contrast to adult blood, contains a population of suppressor T cell precursors that are easily activated by PWM. Irradiation of the cord blood T cells with 2,000 rad eliminated the suppressor activity and revealed normal helper function for immunoglobulin (Ig) G, A, and M when these T cells were co-cultured with adult B cells. Cord blood B cells co-cultured with adult T cells or irradiated cord blood T cells did produce immunoglobulin in response to PWM, but the response was significantly lower than that of adult B cells, and only IgM was produced in these cultures. These studies demonstrate that both the T and B cells of the human newborn have significant functional differences compared with the functions of T and B lymphocyte populations in adults.
Bronchial epithelial cells cultured from clinically stable lung allograft patients promote the development of macrophages from monocytes rather than dendritic cells
Authors: C Ward, K Eger, J Diboll, D Jones, M A Haniffa, M Brodlie, A Fisher, J L Lordan, P A Corris, C M U Hilkens
Journal: Thorax (2009)

It is understood that chronic allograft failure occurs as a result of alloimmune and non-alloimmune injury. Dendritic cells (DC) are thought to be crucial in regulating (allo)immune airway damage and interactions with epithelial cells are likely. Studies in human lung transplantation are limited, however, and the available literature on DC is inconsistent. This study focused on the ex vivo influence of primary bronchial epithelial cells derived from lung allografts on DC differentiation.Epithelial cell conditioned media (ECCM) were added to monocytes differentiating into DC under the influence of interleukin-4 and granulocyte macrophage-colony stimulating factor. The resultant cells were compared with DC cultured without ECCM and with monocyte-derived macrophages. Expression of typical DC (eg, CD1a) and macrophage (eg, CD14) markers was assessed by flow cytometry. Phenotypical assessments were complemented by functional studies of mannose receptor-mediated phagocytosis (FITC-dextran uptake) and antigen-presenting capability (mixed lymphocyte reactions).Cells exposed to ECCM expressed significantly lower levels of CD1a than unexposed DC. CD14 expression and phagocytic function were increased. ECCM cultured cells also expressed lower levels of T cell co-stimulatory molecules, secreted an anti-inflammatory cytokine profile and had significantly reduced antigen-presenting capability.Using phenotypic and functional approaches, this study has shown that ECCM from lung allografts drives the production of macrophage-like cells from monocytes rather than DC. The data suggest that epithelial cells may restrain airway DC and potential alloimmunity. It is unclear whether the observed effect is specifically seen in lung transplant recipients or is a general property of bronchial epithelial cells. This may reflect a homeostatic inter-relationship between airway epithelial and DC populations relevant both to lung allografts and the lung more generally.
Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence
Authors: Benjamin G. Bitler, Jasmine P. Nicodemus, Hua Li, Qi Cai, Hong Wu, Xiang Hua, Tianyu Li, Michael J. Birrer, Andrew K. Godwin, Paul Cairns, Rugang Zhang
Journal: Cancer Research (2011)

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in the United States. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a noncanonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We show that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; P = 0.039) or fallopian tube epithelium (n = 28; P < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (P = 0.003) and predicts shorter overall survival in EOC patients (P = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A/promyelocytic leukemia senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.
Expert second-opinion pathology review of lymphoma in the era of the World Health Organization classification
Authors: M.J. Matasar, W. Shi, J. Silberstien, O. Lin, K.J. Busam, J. Teruya-Feldstein, D.A. Filippa, A.D. Zelenetz, A. Noy
Journal: Annals of Oncology (2011)
Identifying Psychosocial Interventions That Improve Both Physical and Mental Health in Patients With Diabetes
Authors: Elaine Harkness, Wendy Macdonald, Jose Valderas, Peter Coventry, Linda Gask, Peter Bower
Journal: Diabetes Care (2010)

Patients with diabetes suffer high rates of mental health problems, and this combination is associated with poor outcomes. Although effective treatments exist for both diabetes and mental health problems, delivering services for physical and mental health problems separately ignores their interaction and may be inefficient. This systematic review sought to identify psychosocial interventions that could improve both the physical and mental health of patients with diabetes.Studies were identified from the following databases: CENTRAL, MEDLINE, Excerpta Medica (EMBASE), Psychinfo, and Cumulative Index to Nursing and Allied Health Literature (CINAHL). The review included randomized controlled trials in patients with type 1 and type 2 diabetes who received psychosocial interventions and where both mental health and physical health outcomes were reported. Data were extracted on study quality, the content and process of interventions, and outcomes.Eighty-five eligible comparisons were identified, of which 49 reported sufficient data for analysis. Psychosocial interventions modestly improved A1C (standardized mean difference -0.29 [95% CI -0.37 to -0.21]) and mental health outcomes (-0.16 [-0.25 to -0.07]). However, there was a limited association between the effects on A1C and mental health, and no intervention characteristics predicted benefit on both outcomes.Managing physical and mental health in long-term conditions are increasingly important. The review did not identify types of interventions that consistently provide benefits for both physical and mental health. Developing such interventions remains an important challenge. The findings have implications for understanding the interaction between physical and mental health problems and for the coordination of care.
Idiopathic rhinitis, the ongoing quest
Authors: J. B. Van Rijswijk, H. M. Blom, W. J. Fokkens
Journal: Allergy (2005)

The term rhinitis in daily practice is used for nasal dysfunction causing symptoms‐like nasal itching, sneezing, rhinorrhea and or nasal blockage. Chronic rhinitis can roughly be classified into allergic, infectious or nonallergic/noninfectious. When allergy, mechanical obstruction and infections have been excluded as the cause of rhinitis, a number of poorly defined nasal conditions of partly unknown aetiology and pathophysiology remain. The differential diagnosis of nonallergic noninfectious rhinitis is extensive. Although the percentage of patients with nonallergic noninfectious rhinitis with a known cause has increased the last decades, still about 50% of the patients with nonallergic noninfectious rhinitis has to be classified as suffering from idiopathic rhinitis (IR), or rather e causa ignota. Specific immunological, clinical and sometimes radiological and functional tests are required to distinguish known causes. Research to the underlying pathophysiology of IR has moved from autonomic neural dysbalans to inflammatory disorders (local allergy), the nonadrenergic noncholinergic (NANC) sensory peptidergic neural system and central neural hyperaesthesia, still without solid ground or proof. This review summarizes the currently known causes for nonallergic noninfectious rhinitis and possible treatments. Also possible pathophysiological mechanisms of IR are discussed.
Alcohol consumption and alcohol counselling behaviour among US medical students: cohort study
Authors: E. Frank, L. Elon, T. Naimi, R. Brewer
Journal: BMJ (2008)

<b>Objective</b> To determine which factors affect alcohol counselling practices among medical students. <b>Design</b> Cohort study. <b>Setting</b> Nationally representative medical schools (n=16) in the United States. <b>Participants</b> Medical students who graduated in 2003. <b>Interventions</b> Questionnaires were completed (response rate 83%) at the start of students' first year (n=1846/2080), entrance to wards (typically during the third year of training) (n=1630/1982), and their final (fourth) year (n=1469/1901). <b>Main outcome measures</b> Previously validated questions on alcohol consumption and counselling. <b>Results</b> 78% (3777/4847) of medical students reported drinking in the past month, and a third (1668/ 4847) drank excessively; these proportions changed little over time. The proportion of those who believed alcohol counselling was highly relevant to care of patients was higher at entrance to wards (61%; 919/1516) than in final year students (46%; 606/1329). Although students intending to enter primary care were more likely to believe alcohol counselling was highly relevant, only 28% of final year students (391/1393) reported usually or always talking to their general medical patients about their alcohol consumption. Excessive drinkers were somewhat less likely than others to counsel patients or to think it relevant to do so. In multivariate models, extensive training in alcohol counselling doubled the frequency of reporting that alcohol counselling would be clinically relevant (odds ratio 2.3, 95% confidence interval 1.6 to 3.3) and of reporting doing counselling (2.2, 1.5 to 3.3). <b>Conclusions</b> Excessive drinking and binge drinking among US medical students is common, though somewhat less prevalent than among comparably aged adults in the US general population. Few students usually discussed alcohol use with patients, but greater training and confidence about alcohol counselling predicted both practising and believing in the relevance of alcohol counselling. Medical schools should consider routinely training students to screen and counsel patients for alcohol misuse and consider discouraging excessive drinking.
Traitement medical et chirurgical des maladies digestives
Authors: H D Ritchie
Journal: Gut (1983)

Life spans, growth rate, glucose utilisation, response to hydrocortisone, and intracellular activity of lysosomal N-acetyl-beta-glucosaminidase of rheumatoid synovial cells in culture were compared with these properties in nonrheumatoid synovial cells. Except for a small group of RA cells derived from tissue explants, the cells were all isolated by trypsinisation of synovial tissue, either within intact joints or after synovectomy. Cell lines were established by passaging with trypsin. In a study of 56 nonrheumatoid and 24 rheumatoid synovial lines isolated during a 7-year period the latter were found to have a shortened mean life expectancy in culture, though there was wide variation between individual lines. This is in agreement with reported findings from untrypsinised explant-derived synovial lines. However, in the present study mean multiplication rates were identical for nonrheumatoid and rheumatoid synovial cells, and on clear differences could be demonstrated for the other properties studied. No correlation could be found between the life spans of synovial cell lines and the age of the cell donors, whether from rheumatoid or nonrheumatoid sources. Rheumatoid synovial cells isolated from intact joints were notable for especially high proportions of macrophage-like cells and suppression of fibroblasts. In most cases cell lines could not be established from these rheumatoid primary cultures, and in others the lines were short-lived. Early association with relatively high proportions of macrophage-like cells in rheumatoid cultures might thus be important in influencing the establishment and behaviour of synovial cell lines.
Molecular mechanisms of the reversal of imipramine-induced sodium channel blockade by alkalinization in human cardiac myocytes
Authors: Elias Bou-Abboud, Stanley Nattel
Journal: Cardiovascular Research (1998)

Alkalinizing agents reverse cardiotoxicity of a variety of sodium channel blockers, including tricyclic antidepressants, but their mechanisms of action are poorly understood.To establish the mechanisms by which alkalinization diminishes the sodium channel blocking action of imipramine.The whole-cell voltage-clamp technique was used to measure INa during a variety of depolarizing pulse protocols in isolated human atrial myocytes, in the presence and absence of imipramine. A three-state model was used to analyze state-dependent INa block.Imipramine (1 and 5 microM) strongly inhibited INa. Experimental data and piecewise exponential analysis suggested significant binding to both activated and inactivated states. Alkalosis antagonized imipramine-induced INa blockade by increasing the unbinding rate, with intracellular alkalosis being more effective than extracellular alkalosis. The dissociation constant (Kd) for the inactivated state was increased from 0.55 to 1.40 microM by extracellular alkalosis and to 2.51 microM by intracellular alkalosis. Along with the reversal of drug-induced shifts in the inactivation curve, these data indicate that alkalosis on either side of the membrane antagonized drug interactions with the inactivated state. On the other hand, only intracellular alkalosis antagonized activated state block, increasing the Kd from 0.67 microM to 2.18 microM, while extracellular alkalosis left the activated state Kd unaltered at 0.67 microM.Alkalinization antagonizes the INa-blocking action of imipramine by promoting unbinding from the receptor. Intracellular alkalosis has a particularly important effect related to the activated-state interaction. The lipid-soluble, uncharged moiety appears to be a critical determinant of imipramine's ability to dissociate from the Na+ channel receptor.
TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction
Authors: Daniela Ragancokova, Elena Rocca, Anne M.M. Oonk, Herbert Schulz, Elvira Rohde, Jan Bednarsch, Ilse Feenstra, Ronald J.E. Pennings, Hagen Wende, Alistair N. Garratt
Journal: Journal of Clinical Investigation (2014)

The olfactory bulb (OB) receives odor information from the olfactory epithelium and relays this to the olfactory cortex. Using a mouse model, we found that development and maturation of OB interneurons depends on the zinc finger homeodomain factor teashirt zinc finger family member 1 (TSHZ1). In mice lacking TSHZ1, neuroblasts exhibited a normal tangential migration to the OB; however, upon arrival to the OB, the neuroblasts were distributed aberrantly within the radial dimension, and many immature neuroblasts failed to exit the rostral migratory stream. Conditional deletion of Tshz1 in mice resulted in OB hypoplasia and severe olfactory deficits. We therefore investigated olfaction in human subjects from families with congenital aural atresia that were heterozygous for TSHZ1 loss-of-function mutations. These individuals displayed hyposmia, which is characterized by impaired odor discrimination and reduced olfactory sensitivity. Microarray analysis, in situ hybridization, and ChIP revealed that TSHZ1 bound to and regulated expression of the gene encoding prokineticin receptor 2 (PROKR2), a G protein–coupled receptor essential for OB development. Mutations in PROKR2 lead to Kallmann syndrome, characterized by anosmia and hypogonadotrophic hypogonadism. Our data indicate that TSHZ1 is a key regulator of mammalian OB development and function and controls the expression of molecules involved in human Kallmann syndrome.
Recent Natural Selection Identifies a Genetic Variant in a Regulatory Subunit of Protein Phosphatase 2A that Associates with Altered Cancer Risk and Survival
Authors: Lukasz F. Grochola, Alexei Vazquez, Elisabeth E. Bond, Peter Würl, Helge Taubert, Thomas H. Müller, Arnold J. Levine, Gareth L. Bond
Journal: Clinical Cancer Research (2009)

Abstract Purpose: A regulated p53-dependent stress response is crucial in suppressing tumor formation and mediating the response to commonly used cancer therapeutics. However, little is known about the human, inherited genetics of this important signaling pathway. Experimental Design: Studies of human genetic variants in the p53 tumor suppressor gene and MDM2 oncogene have shown that single nucleotide polymorphisms (SNP) can affect p53 signaling, confer cancer risk, and alter outcome, and also suggest that the pathway is under evolutionary selective pressure. Here, we attempt to accelerate the identification of functional p53 pathway SNPs by incorporating these characteristics into an analysis of 142 genes that are known to affect p53 signaling. Results: We report that a genomic scan for recent natural selection denotes that of the 142 genes studied, the PPP2R5E gene that encodes a regulatory subunit of the tumor suppressing protein phosphatase 2A resides in a naturally selected genomic region. We go on to show that a selected SNP in PPP2R5E (ϵ-SNP2) associates with significant allelic differences in the onset (up to 19.2 years; P = 0.0002) and risk (odds ratio, up to 8.1; P = 0.0009) of soft tissue sarcoma development, as well as overall survival (relative risk, up to 3.04; P = 0.026). Conclusions: The PPP2R5E gene is identified as harboring genetic variants that can affect human cancer and are possibly under evolutionary selection pressure. (Clin Cancer Res 2009;15(19):6301–8)
In Vitro Models of Traumatic Brain Injury
Authors: Barclay Morrison, Benjamin S. Elkin, Jean-Pierre Dollé, Martin L. Yarmush
Journal: Annual Review of Biomedical Engineering (2011)

In vitro models of traumatic brain injury (TBI) are helping elucidate the pathobiological mechanisms responsible for dysfunction and delayed cell death after mechanical stimulation of the brain. Researchers have identified compounds that have the potential to break the chain of molecular events set in motion by traumatic injury. Ultimately, the utility of in vitro models in identifying novel therapeutics will be determined by how closely the in vitro cascades recapitulate the sequence of cellular events that play out in vivo after TBI. Herein, the major in vitro models are reviewed, and a discussion of the physical injury mechanisms and culture preparations is employed. A comparison between the efficacy of compounds tested in vitro and in vivo is presented as a critical evaluation of the fidelity of in vitro models to the complex pathobiology that is TBI. We conclude that in vitro models were greater than 88% predictive of in vivo results.
In Vivo Survival of Viral Antigen–specific T Cells that Induce Experimental Autoimmune Encephalomyelitis
Authors: Rafael L. Ufret-Vincenty, Laura Quigley, Nancy Tresser, Seong Hee Pak, Ameer Gado, Stefan Hausmann, Kai W. Wucherpfennig, Stefan Brocke
Journal: The Journal of Experimental Medicine (1998)

A peptide derived from the human papillomavirus L2 protein is recognized by a myelin basic protein (MBP)-specific T cell clone from a multiple sclerosis patient and by MBP-specific autoantibodies purified from multiple sclerosis brain tissue. We now show in mice that low doses of this papillomavirus peptide were optimal in selecting a subpopulation of papillomavirus peptide–specific T cells that cross-reacted with MBP(87–99) and with an unrelated viral peptide derived from the BSLF1 protein of Epstein-Barr virus (EBV). These low dose viral peptide– specific T cell lines were highly encephalitogenic. Splenocytes from mice transferred with viral peptide–specific T cells showed a vigorous response to both the papillomavirus and MBP peptides, indicating that viral antigen–specific T cells survived for a prolonged time in vivo. The EBV peptide, unable to prime and select an autoreactive T cell population, could still activate the low dose papillomavirus peptide–specific cells and induce central nervous system (CNS) autoimmunity. Cytokine profiles of papillomavirus peptide–specific encephalitogenic T cells and histopathology of CNS lesions resembled those induced by MBP. These results demonstrate conserved aspects in the recognition of the self-antigen and a cross-reactive viral peptide by human and murine MBP-specific T cell receptors. We demonstrate that a viral antigen, depending on its nature, dose, and number of exposures, may select autoantigen-specific T cells that survive in vivo and can trigger autoimmune disease after adoptive transfer.
NORE1B Is a Putative Tumor Suppressor in Hepatocarcinogenesis and May Act via RASSF1A
Authors: Doris Macheiner, Christine Gauglhofer, Chantal Rodgarkia-Dara, Michael Grusch, Andreas Brachner, Christoph Bichler, Daniela Kandioler, Hedwig Sutterlüty, Wolfgang Mikulits, Rolf Schulte-Hermann, Bettina Grasl-Kraupp
Journal: Cancer Research (2008)

Abstract Recently, we found epigenetic silencing of the Ras effector genes NORE1B and/or RASSF1A in 97% of the hepatocellular carcinoma (HCC) investigated. This is strong evidence that the two genes are of major significance in hepatocarcinogenesis. Although RASSF1A serves as a tumor suppressor gene, the functions of NORE1B are largely unknown. Here, we studied the role of NORE1B for growth and transformation of cells. To understand the molecular mechanisms of action of the gene, we used the wild-type form and deletion mutants without the NH2 terminus and CENTRAL domain, the Ras association (RA) domain, or the COOH-terminal SARAH-domain. Intact RA and SARAH-domains were found to be necessary for NORE1B (a) to increase the G0-G1 fraction in hepatoma cells, (b) to suppress c-Myc/Ha-Ras–induced cell transformation, and (c) to interact closely with RASSF1A, as determined with fluorescence resonance energy transfer. In further studies, cell cycle delay by NORE1B was equally effective in hepatocyte cell lines with wild-type or mutant Ras suggesting that NORE1B does not interact with either Ras. In conclusion, NORE1B suppresses replication and transformation of cells as effectively as RASSF1A and thus is a putative tumor suppressor gene. NORE1B interacts physically with RASSF1A and functional loss of one of the interacting partners may lead to uncontrolled growth and transformation of hepatocytes. This may explain the frequent epigenetic silencing of NORE1B and/or RASSF1A in HCC. [Cancer Res 2009;69(1):235–42]